Medical Sciences Forum

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1 pages, 187 KiB

Open AccessAbstract

Hepatoprotective Effect of the N-Alkylated Isobornylamine against CCl4-Induced Chronic Liver Damage in Mice

by Darya Pon`kina, Sergey Kuranov, Nataliya Zhukova, Yulia Meshkova, Mikhail Khvostov, Olga Luzina, Tatyana Tolstikova and Nariman Salakhutdinov

Med. Sci. Forum 2022, 14(1), 1; https://doi.org/10.3390/ECMC2022-13152 - 1 Nov 2022

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by impaired lipid and carbohydrate metabolism, and is characterized by fatty degeneration, necrosis, inflammation, and fibrosis of hepatocytes. There are currently no approved drugs for the treatment of NAFLD, so their search [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by impaired lipid and carbohydrate metabolism, and is characterized by fatty degeneration, necrosis, inflammation, and fibrosis of hepatocytes. There are currently no approved drugs for the treatment of NAFLD, so their search remains an urgent task for present pharmacology. Previously, N-alkylated isobornylamine (compound 1), a GPR40 agonist, at a dose of 30 mg/kg was shown to resolve fatty liver degeneration in C57Bl/6^Ay mice and improve glucose tolerance. As a result, we continued to study the hepatoprotective effect of compound 1 on CCl₄-induced chronic hepatotoxicity model in CD-1 mice. Compound 1 was administered per os at doses of 60, 90, 120 and 150 mg/kg daily for 3 weeks, as well as the reference drug silymarin at a dose of 100 mg/kg. At the end of the experiment, a biochemical blood assay was carried out, which showed that compound 1 dose-dependently reduces ALT, AST and ALKP. According to the results of a histological and morphometry liver examination, compound 1 was found to reduce the severity of degenerative-necrotic changes in hepatocytes. More pronounced improvements in doses of 120 and 150 mg/kg were noted. Thus, isobornylamine derivative exhibits a hepatoprotective effect not only in metabolic liver injury, but also in CCl₄-induced chronic liver damage. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 194 KiB

Open AccessAbstract

Stochastic Dynamics Mass Spectrometric 3D Structural Analysis of N-Glycans of Fetal Bovine Serum—An Experimental and Theoretical Study

by Bojidarka Ivanova and Michael Spiteller

Med. Sci. Forum 2022, 14(1), 2; https://doi.org/10.3390/ECMC2022-12870 - 12 Aug 2022

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Abstract

This study addresses the problem of performing mass spectrometric (MS), 3D molecular and electronic structural analyses of glycans mixtures from fetal bovine serum. This undertaking is unexpectedly difficult, due to: random variation of non-template-driven glycosylation and fucosylation processes; a lack of regioselective derivatization [...] Read more.

This study addresses the problem of performing mass spectrometric (MS), 3D molecular and electronic structural analyses of glycans mixtures from fetal bovine serum. This undertaking is unexpectedly difficult, due to: random variation of non-template-driven glycosylation and fucosylation processes; a lack of regioselective derivatization for mixtures of polydisperse glycans towards length and skeletal modifications; isomers of oligomers and polymers, including linear and branching molecular structures, respectively. These factors significantly increase the difficulty in glycan structural analysis using mass spectrometry. Furthermore, MS phenomena of carbohydrates include reactions of intramolecular rearrangement and cyclization, proton and charge transfer effects, noncovalently bound self-associations, alkali metal ion adducts, and multiply charged species under the tandem MS/MS operation mode. However, this study presents a plausible solution to the problem. It employs our innovative stochastic dynamic MS model formula D^”_SD = 2.6388.10⁻¹⁷. (<I²>–<I>²) that is capable of accurately quantifying the fluctuations and temporal behavior of measurable variable intensity (I) of analyte peaks. It has been shown that it can accurately and directly quantify analyte concentrations in solution and determine 3D molecular and electronic structures. This latter task is less straightforward. It employs the Arrhenius model equation within the framework of his transition state theory and the power capability of quantum chemical methods. The validity of the latter statements is examined, herein. This study, first, comes to grips with MS collision-induced dissociation phenomena of mixtures of 2-aminobenzamide-derivatized glycans. It utilizes ab initio and DFT static, molecular dynamics, molecular mechanics, and chemometrics. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 196 KiB

Open AccessAbstract

Molecular Modeling and Synthesis of New HIV Latency-Reversing Agents Targeting the Lymphatic System

by Beatriz Meduqui Rodrigues, Juliana Romano Lopes, Andressa Francielli Bonjorno and Jean Leandro dos Santos

Med. Sci. Forum 2022, 14(1), 3; https://doi.org/10.3390/ECMC2022-13149 - 1 Nov 2022

Viewed by 742

Abstract

During the HIV infection, a small amount of the virus remains in a latent state, forming a viral reservoir in places with limited access to drugs such as lymph nodes. HIV latency reversing agents, as HDAC inhibitors, have been used in the “kick [...] Read more.

During the HIV infection, a small amount of the virus remains in a latent state, forming a viral reservoir in places with limited access to drugs such as lymph nodes. HIV latency reversing agents, as HDAC inhibitors, have been used in the “kick and kill” strategy aiming to reactivate the latent virus and its subsequent elimination. Combining these compounds with a lipophilic group may promote an increase in lipophilicity and improve the bioavailability. In order to target these compounds to lymphatic system, we described the design, synthesis and evaluation of pro-drugs of HDAC-3 inhibitors. In silico studies were performed using the molecular modelling Maestro by Schrödinger environment using HDAC-3 (PDB: 4A69). All compounds were prepared through divergent synthesis. The reactions consisted of NH₂ protection in 5-fluoro 2-nitroaniline reagent using di-tert-butyl dicarbonate, reduction of the NO₂ group with Fe and NH₄Cl/MeOH and coupling reactions using HATU/DIPEA or oxalyl chloride with palmitic and α-linolenic acid. LogP values were determined by HPLC-UV (C18, MeOH:H2O). Docking simulation suggests that all compounds are able to interact with HDAC-3, with docking score values of −6.078 to −8.369. Four compounds were synthesized at global yields ranging from 21–68%. All structures were characterized by analytical methods. LogP values were determined ranging from 4.89–6.5. Pro-drug compounds were designed and synthesized. The results of in silico studies and experimental LogP justify that these compounds can be targeted to the lymphatic system, to act as HDAC-3 inhibitors. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 184 KiB

Open AccessAbstract

Thiazolopyrimidine as a Promising Anticancer Pharmacophore: In Silico Drug Design, Molecular Docking and ADMET Prediction Studies

by Omar A. El-Khouly, Dina I. A. Othman, Amany S. Mostafa and Mohammed A. M. Massoud

Med. Sci. Forum 2022, 14(1), 4; https://doi.org/10.3390/ECMC2022-13313 - 1 Nov 2022

Viewed by 851

Abstract

Thiazolopyrimidines are well known to be designed to act as bio-isosteric analogues of purine nucleus. They proved to show a wide range of biological activities, such as anticancer, anti-inflammatory, antifungal, antiviral and antitubercular activity. In this study, a literature survey was thoroughly performed [...] Read more.

Thiazolopyrimidines are well known to be designed to act as bio-isosteric analogues of purine nucleus. They proved to show a wide range of biological activities, such as anticancer, anti-inflammatory, antifungal, antiviral and antitubercular activity. In this study, a literature survey was thoroughly performed to elect the most active thiazolopyrimidine-containing scaffolds, acting as anticancer agents, to be subjected to extensive computational studies in order to explore the possible credible mode of their anticancer activity. First, drug-likeness was investigated for the most active derivatives, followed by molecular docking study against Cyclin-dependent kinases (CDK), Vascular endothelial growth factor receptor (VEGFR) and Phosphoinositide 3-kinases (PI3K) enzymes in order to assess their binding energy and propose the mode of action. Next, contact preference and surface mapping studies were carried out to explain the presence of remarkable affinity of certain analogues towards a specific enzyme, in addition to providing more information about their activity. Finally, physicochemical properties, Lipinski’s rule of five and ADMET prediction studies were applied to predict the best route of administration and to suggest the pharmacokinetics of the most promising candidates. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 198 KiB

Open AccessAbstract

Phytochemical and Pharmacological Profile of Four Malagasy Medicinal Plants Used in Different Chronic Diseases: Strategies for the Sustainable Use of Natural Resources in the Malagasy Health System

by Zoarilala Rinah Razafindrakoto, Nantenaina Tombozara, Dario Donno, Gabriele Loris Beccaro and David Ramanitrahasimbola

Med. Sci. Forum 2022, 14(1), 5; https://doi.org/10.3390/ECMC2022-13160 - 1 Nov 2022

Viewed by 802

Abstract

Traditional medicine plays an important role in the Malagasy health system. In Madagascar, medicinal plants are the main remedies for several diseases, especially chronic diseases. Scientific studies are performed to valorize the use of Imperata cylindrica (Ic), Uapaca bojeri (Ub), Vaccinium secondiflorum (Vs), [...] Read more.

Traditional medicine plays an important role in the Malagasy health system. In Madagascar, medicinal plants are the main remedies for several diseases, especially chronic diseases. Scientific studies are performed to valorize the use of Imperata cylindrica (Ic), Uapaca bojeri (Ub), Vaccinium secondiflorum (Vs), and Ravenala madagascariensis (Rm). Ic and Ub are used to treat some inflammatory-related diseases, Vs has an anti-diabetic value, and Rm is known as an antihypertensive. Phytochemical and pharmacological studies were carried out using standard scientific models to justify their properties. Firstly, the antioxidant, analgesic, anti-inflammatory, and/or vasorelaxant activities of their crude methanol extracts (ME) were evaluated according to ethnomedicinal information. The ME of Ic, Ub, and Vs showed potent antioxidant activities on DPPH and FRAP methods. These species are rich in phenolics, flavonoids, and organic acids, known for their antioxidant activities. They also possess significant analgesic and anti-inflammatory activities, respectively, assessed on the pain model caused by acetic acid (1%) and on inflammatory edema induced by carrageenan in mice. Sitostenone was isolated as an analgesic and anti-inflammatory compound from Ic. Ub and Vs ME significantly reduced the glycemia level after 30 min of glucose loading in mice compared to glibenclamide. Androsta-1,4-dien-3,16-dione was isolated as the vasorelaxant molecule from Rm, responsible for its antihypertensive activity. These results showed that there are some scientific reasons that can justify the therapeutic properties of these plants. It is very important to investigate the local use of biodiversity to identify new bioactive compounds, to support biodiversity conservation and sustainable development projects in Madagascar. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Synthesis, ADME/T, and Carbonic Anhydrase Binding of Hydroxycarboxamide Compounds

by Abdeslem Bouzina, Yousra Ouafa Bouone, Rachida Mansouri and Nour-Eddine Aouf

Med. Sci. Forum 2022, 14(1), 6; https://doi.org/10.3390/ECMC2022-13446 - 1 Nov 2022

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Abstract

The interconversion of carbon dioxide and the bicarbonate ion is carried out by carbonic anhydrases (CA), which are ubiquitous metalloenzymes with Zn in their active site. Disorder of CA enzymes can cause several diseases such as glaucoma, epilepsy, obesity, and cancer. Many existing [...] Read more.

The interconversion of carbon dioxide and the bicarbonate ion is carried out by carbonic anhydrases (CA), which are ubiquitous metalloenzymes with Zn in their active site. Disorder of CA enzymes can cause several diseases such as glaucoma, epilepsy, obesity, and cancer. Many existing drugs have shown effective inhibition of CAs including Acetazolamide, Dorzolamide, Methazolamide, and Valdecoxib. In order to conceive new agents inhibiting CAs, two small molecules were synthesized and characterized by the usual spectroscopic methods. The prepared compounds were obtained by the condensation of dimedone and cyclohexanedione with CSI (chlorosulfonyl isocyanate) in the presence of methanol as a proton donor. The synthesized derivatives contain a primary amide group (CONH₂) bio-isostere of the sulfonamide group (SO₂NH₂) which is present in the quasi-totality of CAs inhibitors. The interactions between our new synthesized molecules and the active site of CAII were determined using docking simulation (PDB: 2AW1); the results showed great stability of these compounds inside the active site with the presence of metallic and hydrogen bonds similar to the ones present between CAII and the reference Valdecoxib. Pharmacokinetic properties and toxicity were predicted using in silico tool SwissADME and Molsoft. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 160 KiB

Open AccessAbstract

Development of Bioactive Molecules for the Treatment of Alzheimer’s Disease

by Amisha Punmiya, Ruchita Gharat and Arati Prabhu

Med. Sci. Forum 2022, 14(1), 7; https://doi.org/10.3390/ECMC2022-13470 - 1 Nov 2022

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Abstract

A series of novel thiophene pyrazolines were designed as potential bioactive molecules against Alzheimer’s disease. The probable binding modes of these molecules in AChE were evaluated using in silico techniques, and promising molecules were then synthesized and characterized. Their biological activities were profiled [...] Read more.

A series of novel thiophene pyrazolines were designed as potential bioactive molecules against Alzheimer’s disease. The probable binding modes of these molecules in AChE were evaluated using in silico techniques, and promising molecules were then synthesized and characterized. Their biological activities were profiled to confirm their potential as multifunctional molecules for the treatment of Alzheimer’s disease by addressing multiple pathological mechanisms. While the anti-oxidant activities of the synthesized molecules needed further optimization, the series showed excellent potential in mitigating the multiple causative factors via Aβ aggregation inhibition, AChE inhibition, metal chelation, and inhibition of advanced glycation products. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 187 KiB

Open AccessAbstract

Study of Cytotoxicity of Spiro-Fused [3-Azabicyclo[3.1.0]hexane]oxindoles against Tumor Cell Lines

by Anton A. Kornev, Stanislav V. Shmakov, Alexey S. Klyuchnikov, Alexey V. Artemov, Alexander V. Stepakov and Vitali M. Boitsov

Med. Sci. Forum 2022, 14(1), 8; https://doi.org/10.3390/ECMC2022-13653 - 16 Nov 2022

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Abstract

Oncological diseases are one of the most common public health problems and the second leading cause of death after cardiovascular disease. Natural products or synthetic compounds derived from natural products continue to be excellent sources for new drug candidates. Recent advances in synthesis [...] Read more.

Oncological diseases are one of the most common public health problems and the second leading cause of death after cardiovascular disease. Natural products or synthetic compounds derived from natural products continue to be excellent sources for new drug candidates. Recent advances in synthesis of complex heterocyclic systems have led to significant increase in interest in development of efficient methods for synthesis of thereof as potential drugs or biological probes. Oxindole, azabicyclohexane and pyrrolizine units are known heterocyclic motifs that form the core of a large family of alkaloid natural products with strong bioactivity profiles. Series of heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework have been studied for their antiproliferative activity against K562, Jurkat, HeLa, and CT26 cell lines. These spiro-fused adducts are readily available via one-pot three-component 1,3-dipolar cycloaddition reactions of cyclopropenes and azomethine ylides (generated in situ from amino acids and oxindoles). In agreement with DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm in up to 40% of treated cells. In addition, we discovered that the number of cells with filopodium-like membrane protrusions was significantly reduced after treatment with some of the tested compounds (from 92% in control cells up to 36% after treatment). The obtained results support the antitumor effect of the studied compounds and encourage the extension of the study in order to improve the anticancer activity and reduce the toxicological risks of the obtained compounds. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 188 KiB

Open AccessAbstract

In Vitro Evaluation of Rare-Earth-Doped Phosphor Nanoparticles to Assess Their Antitumoral Efficiency on Lung Cancer Cells

by Miruna S. Stan, Ionela Cristina Voinea and Sorina Nicoleta Voicu

Med. Sci. Forum 2022, 14(1), 9; https://doi.org/10.3390/ECMC2022-13312 - 1 Nov 2022

Viewed by 846

Abstract

Rare-earth-doped nanoparticles have been investigated for their use in disease diagnosis, drug delivery, tumor therapy and bioimaging. In this context, we selected BaSO₄:Eu phosphor nanoparticles, commercially available from Merck (Darmstadt, Germany), to evaluate their antitumoral efficiency for prospective therapeutic applications, as [...] Read more.

Rare-earth-doped nanoparticles have been investigated for their use in disease diagnosis, drug delivery, tumor therapy and bioimaging. In this context, we selected BaSO₄:Eu phosphor nanoparticles, commercially available from Merck (Darmstadt, Germany), to evaluate their antitumoral efficiency for prospective therapeutic applications, as no study was previously performed. Lung carcinoma epithelial cells (A549 cell line) were incubated with barite (BaSO₄) nanophosphors for up to 72 h. The highest concentration of nanoparticles tested (200 µg/mL) decreased the number of viable cells only by 10% compared to controls, as measured using the (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) test. This result was also confirmed by the double staining of viable and dead cells with calcein-AM and ethidium homodimer, respectively. In addition, the level of nitric oxide released by the cells in the media after incubation with the nanoparticles increased by 10% compared to controls, showing that no major inflammation was induced even in the presence of high concentrations of particles. However, an increased accumulation of lysosomes was noticed with LysoTracker Green DND-26 (Invitrogen^TM, Waltham, MA, USA) in a time- and dose-dependent manner. This finding could suggest that the cells are further eliminating Eu-doped barite particles via their uptake by these acidic organelles. In conclusion, our investigation revealed no significant anti-proliferative effects of BaSO₄:Eu phosphor nanoparticles on lung tumor cells, but further investigations related to their cytotoxicity should be performed for a better characterization in a biological environment. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 206 KiB

Open AccessAbstract

Cytotoxic Activity of Schinus molle L. Berries and Leaves

by Selen İlgün and Gökçe Şeker Karatoprak

Med. Sci. Forum 2022, 14(1), 10; https://doi.org/10.3390/ECMC2022-13311 - 1 Nov 2022

Viewed by 855

Abstract

Schinus molle is a perennial tree commonly known as “Pirul” in Mexico. This aromatic plant belongs to the Anacardiaceae family and the antibacterial, antifungal, insecticidal and cytotoxic activities of its bioactive essential oils have been previously investigated. Locally, the plant is mainly used [...] Read more.

Schinus molle is a perennial tree commonly known as “Pirul” in Mexico. This aromatic plant belongs to the Anacardiaceae family and the antibacterial, antifungal, insecticidal and cytotoxic activities of its bioactive essential oils have been previously investigated. Locally, the plant is mainly used as an analgesic, antiseptic, antibacterial, purgative and diuretic agent. In this study, the plant, which is generally grown as an ornamental plant on the Mediterranean coast of Turkey, was evaluated in terms of its cytotoxic properties based on its secondary metabolites. Raw and ripe fruits, together with the plant’s leaves, were collected and extracted using different solvents. Both 70% methanol and water extracts of leaves, ripe fruits and raw fruits were prepared. The six different extracts obtained were tested in cell lines of humans’ most common cancer types (Du-145 prostate cancer, CaCo-2 colon cancer and MCF-7 breast cancer). As a result, methanol extracts prepared from the ripe fruits of the plant decreased the viability of three different cancer cells, especially MCF-7 and Du-145 cell lines, at low concentrations below 50%. Particularly in the MCF-7 cell line, the viability at 15 µg/mL was calculated as 46.03 ± 1.19%. While the cell line which was least effected by the extracts was CaCo-2, the extracts with the most negligible antiproliferative effect were the water extracts of the leaves and the raw and ripe fruits. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 186 KiB

Open AccessAbstract

Late-Stage Oxygenation towards the Preparation of Metabolites of Agrochemical Active Ingredients

by Duarte B. Clemente, Carlos M. Monteiro and Jaime A. S. Coelho

Med. Sci. Forum 2022, 14(1), 11; https://doi.org/10.3390/ECMC2022-13261 - 1 Nov 2022

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Abstract

The development of plant protection products requires the safety profile analysis of active ingredients (AIs). This includes the toxicity determination of AI metabolites. A very common phase-one metabolism reaction is C-oxygenation catalyzed by cytochrome P450 enzymes. Thus, the synthesis of oxygenated AI metabolites [...] Read more.

The development of plant protection products requires the safety profile analysis of active ingredients (AIs). This includes the toxicity determination of AI metabolites. A very common phase-one metabolism reaction is C-oxygenation catalyzed by cytochrome P450 enzymes. Thus, the synthesis of oxygenated AI metabolites is of great importance to agrochemical producing companies, namely ASCENZA Agro, for safety evaluation purposes. Herein, we describe the progress towards the synthesis of hydroxylated aromatic metabolites of several AIs using methods described by Tobias Ritter and co-workers. These methods allow the late-stage oxygenation of the aromatic and benzylic positions by generating mesylate derivatives with bis(methanesulfonyl) peroxide as an oxidant, followed by conversion to the corresponding phenols. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 207 KiB

Open AccessAbstract

2-Styrylchromones Inhibit IL-1β-Induced Inflammatory Mediators’ Production in Human Fibroblast-like Synoviocytes

by Ana Teresa Rufino, Mariana Lucas, Artur M. S. Silva, Eduarda Fernandes and Daniela Ribeiro

Med. Sci. Forum 2022, 14(1), 12; https://doi.org/10.3390/ECMC2022-13183 - 1 Nov 2022

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Abstract

Rheumatoid arthritis (RA) is a progressive and chronic autoimmune disease that is characterized by persistent synovial inflammation and irreversible cartilage and bone damage that affects the synovial joints and adjacent tissues. Presently, effective drugs that can control RA process remain an unmet need. [...] Read more.

Rheumatoid arthritis (RA) is a progressive and chronic autoimmune disease that is characterized by persistent synovial inflammation and irreversible cartilage and bone damage that affects the synovial joints and adjacent tissues. Presently, effective drugs that can control RA process remain an unmet need. The role of fibroblast-like synoviocytes (FLS) on synovial inflammation initiation and progression makes these cells natural targets for the search for new effective molecules to stop disease progression. 2-Styrylchromones (2-SC) feature a wide range of biological properties, including antioxidant and anti-inflammatory activities. The present study investigates the effect of six hydroxylated and methoxylated 2-SC on the IL-1β-induced increase of ^•NO and iNOS levels in human FLS, pointing the role of NF-κB activation in the process. From the tested 2-SC, the one presenting two OCH₃ at C-5 and C-7 on A-ring and a catechol group on B-ring, significantly reduced iNOS expression and ^•NO production. These effects seemed to be partially mediated by the reversion of IL-1β-induced cytoplasmic IkBα disappearance and nuclear p65 increase. These findings may be of great value in the development of new 2-SC which should be further explored and carefully evaluated to reveal their full potential on the treatment of RA. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 206 KiB

Open AccessAbstract

Porphyrin-IgG Photoimmunoconjugates for Photodynamic Inactivation against Staphylococus aureus

by Rocio Belén Acosta, Edgardo Néstor Durantini and Mariana Belén Spesia

Med. Sci. Forum 2022, 14(1), 13; https://doi.org/10.3390/ECMC2022-13259 - 1 Nov 2022

Viewed by 697

Abstract

Photodynamic inactivation (PDI) is a therapeutic approach based on combined use of light, oxygen, and a photosensitizing agent (PS). These three components interact to generate reactive oxygen species, which are cytotoxic and irreversibly damage vital components of microbial cells, leading to death. However, [...] Read more.

Photodynamic inactivation (PDI) is a therapeutic approach based on combined use of light, oxygen, and a photosensitizing agent (PS). These three components interact to generate reactive oxygen species, which are cytotoxic and irreversibly damage vital components of microbial cells, leading to death. However, this methodology has not managed to be completely specific in its mode of action since the photosensitizer can bind to both pathogenic and commensal microorganisms and even to host cells. Since subsequent irradiation of such cells could lead to their destruction, it is desirable to direct the photodynamic activity to the target cell. Therefore, the objective of this work was to direct the destruction of pathogenic microorganisms without affecting the normal flora. This could be achieved by binding the photosensitizing molecule to an antibody against the surface of the target organism. Therefore, a TCPP-IgG conjugate was synthesized using 4,4′,4″,4‴-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (TCPP) and the antibody anti-protein A of Staphylococcus aureus. The UV-visible spectra of TCPP-IgG showed the typical Soret and Q bands characteristic of porphyrin derivatives and, additionally, a new band was observed, corresponding to the absorbance of the protein. However, the results indicated that the conjugation reaction affects the photochemical properties of fluorescent emission and the production of reactive oxygen species compared to TCPP free base. As a consequence, a lower cytotoxicity was observed in planktonic cells of S. aureus. PDI can become a promising therapeutic alternative, having as a strategy the specific control of bacterial death for an efficient eradication. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 168 KiB

Open AccessAbstract

Investigation of Pyrazoline-Based Aromatic Sulfamates as Carbonic Anhydrase Isoforms I, II, IX, and XII Inhibitors

by Davide Moi

Med. Sci. Forum 2022, 14(1), 14; https://doi.org/10.3390/ECMC2022-13257 - 1 Nov 2022

Viewed by 604

Abstract

Four new series of aromatic sulfamates were synthesized and investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase, hCA I, II, IX, and XII. The reported derivatives, obtained through the sulfamoylation reaction of the corresponding [...] Read more.

Four new series of aromatic sulfamates were synthesized and investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase, hCA I, II, IX, and XII. The reported derivatives, obtained through the sulfamoylation reaction of the corresponding phenolic precursors, bear 3,5-diarylpyrazoline moieties as spacers between the benzenesulfamate fragment, which binds the zinc ion from the active site as well as from the tail of the inhibitor. Pyrazolines are biologically privileged scaffolds, endowed with a versatile biological activity, such as an anti-proliferative action. The derivatives were tested for the inhibition of the cytosolic in the hCA I and II (off-target isoforms) and the transmembrane, as well as in the tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally, the hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evident in the hCA II (KIs in the range of 0.42–90.1 nM), IX (KIs in the range of 0.72–63.6 nM), and XII (KIs in the range of 0.88–85.2 nM). The best substitution fragments at the pyrazoline ring included: for the CA II, a 4-sulfamic group on the 3-aryl, the halogens on the 5-aryl, a methoxy group on the 3-aryl, and a 4-sulfamate group on the 5-aryl; for the CA IX and the CA XII, they included the sulfamic group on the 3- or 4-position of the 5-aryl and an electron-withdrawing group on the 4-postion of the 3-aryl ring. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 177 KiB

Open AccessAbstract

First-in-Class, Thiosemicarbazide-Based, Dual Inhibitors of Human DNA Topoisomerase IIα and Indoleamine-2,3-Dioxygenase 1 (IDO-1) with Strong Anticancer Properties

by Barbara Kaproń and Tomasz Plech

Med. Sci. Forum 2022, 14(1), 15; https://doi.org/10.3390/ECMC2022-13268 - 1 Nov 2022

Viewed by 679

Abstract

According to a WHO report from 2020, cancer constitutes one of the leading causes of death worldwide. The number of cancer deaths is estimated to be approximately 10 million per year. These epidemiological data confirm that cancer is an increasingly global healthcare problem [...] Read more.

According to a WHO report from 2020, cancer constitutes one of the leading causes of death worldwide. The number of cancer deaths is estimated to be approximately 10 million per year. These epidemiological data confirm that cancer is an increasingly global healthcare problem that needs urgent action. From a biological point of view, the basic feature of cancer is the uncontrolled growth and spread of abnormal cells from the place of origin to another part of the body. Inhibition of uncontrolled proliferation is one of the main goals of anticancer therapy. During our preliminary studies, we identified a group of thiosemicarbazide-based human DNA topoisomerase II inhibitors that decreased the viability of cancer cells and inhibited intracellular biosynthesis of their DNA much stronger than etoposide, i.e., clinically relevant topoisomerase II inhibitor. What is also important isthat the investigated compounds were recognized as topoisomerase II poisons because of their ability to stabilize the DNA-topoII cleavable complex. The investigated thiosemicarbazide derivatives were examined as potential anticancer agents against a panel of ten cancer cell lines. Moreover, we have discovered and described the first-in-class dual inhibitors of human DNA topoisomerase II/indoleamine-2,3-dioxygenase 1 (IDO1) that can lead to the future use of thiosemicarbazide derivatives as relevant components of anticancer immunotherapy. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 169 KiB

Open AccessAbstract

Small Molecule Inhibitors of Bacterial Quorum Sensing

by Timothy P. O’Sullivan

Med. Sci. Forum 2022, 14(1), 16; https://doi.org/10.3390/ECMC2022-13264 - 1 Nov 2022

Cited by 1 | Viewed by 640

Abstract

Quorum sensing is a bacterial mechanism that is essential in the pathogenesis of many infections, such as P. aeruginosa. These infections are strongly influenced by specific quorum sensing molecules, such as Autoinducer-2 (AI-2). AI-2 binds to quorum sensing receptors within bacteria, leading [...] Read more.

Quorum sensing is a bacterial mechanism that is essential in the pathogenesis of many infections, such as P. aeruginosa. These infections are strongly influenced by specific quorum sensing molecules, such as Autoinducer-2 (AI-2). AI-2 binds to quorum sensing receptors within bacteria, leading to the up-regulation of virulence genes that cause biofilm formation and toxin production. Naturally-occurring brominated furanones isolated from the marine algae Delisea pulchra were previously found to possess properties which inhibited bacterial quorum sensing in AI-2 sensitive species. The aim of this work was to create a series of novel halogenated furanones which can function as quorum sensing inhibitors of AI-2. Based on the lead from Delisea pulchra, a library of compounds was synthesised via the functionalisation of gem-dibromoolefin and gem-dichloroolefin intermediates using palladium-catalysed couplings, namely Suzuki and Sonogashira reactions. These compounds were subsequently evaluated for their effects on biofilm formation in selected microbes. Several molecules were confirmed to be highly effective biofilm inhibitors in multiple pathogens, including P. aeruginosa and C. albicans. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 176 KiB

Open AccessAbstract

The Effect of the Composition of Leuzea and Cranberry Meal Extracts on Physical Performance

by Daria Khalikova, Sergey An’kov and Tatyana Tolstikova

Med. Sci. Forum 2022, 14(1), 17; https://doi.org/10.3390/ECMC2022-13274 - 1 Nov 2022

Cited by 1 | Viewed by 758

Abstract

Over the last decade, a huge number of herbal supplements have been introduced into the practice of sports medicine in order to increase physical performance. Medicinal plants are a valuable source of a large number of secondary metabolites, such as polyphenols, triterpenes and [...] Read more.

Over the last decade, a huge number of herbal supplements have been introduced into the practice of sports medicine in order to increase physical performance. Medicinal plants are a valuable source of a large number of secondary metabolites, such as polyphenols, triterpenes and adaptogens. This determines the ability of herbal medicines to compensate for the deficiency of nutrients in the human body. The use of secondary products of processing provides an opportunity to obtain additional products of high biological value, and to purposefully spend natural resources’ reserves. Based on the literature data on the properties of leuzea and ursolic acid, the researchers of the Laboratory of Pharmacological Research NIOCH SB RAS developed a composition of two plant components: extracts of leuzea and cranberry meal, containing 0.31% ecdysten and 40% ursolic acid, respectively. The aim of this work is to study the effect of the composition of leuzea and cranberry meal extracts and its individual components on performance in a treadmill test in male CD-1 mice. To confirm the increase in physical performance, the concentration of lactate and blood glucose was determined. After a seven-day acclimation, test compounds were administered daily for two weeks, with all mice receiving exercise (at least 24 h between each run). At the end of the experiment, the concentration of lactate and glucose in the blood was measured. The composition of leuzea and cranberry meal extracts significantly reduced the concentration of lactate and glucose in the blood, indicating its ability to increase physical performance. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 171 KiB

Open AccessAbstract

Application of Both Cluster and Principal Component Analysis for Evaluation of the Lipophilicity Parameters of Selected Antiandrogen Drugs

by Dawid Wardecki, Małgorzata Dołowy and Katarzyna Bober-Majnusz

Med. Sci. Forum 2022, 14(1), 18; https://doi.org/10.3390/ECMC2022-13262 - 1 Nov 2022

Viewed by 748

Abstract

The aim of this work was the use of both cluster analysis (CA) and Principal Component Analysis (PCA) for the evaluation of the lipophilicity of selected antiandrogen drugs such as abiraterone, bicalutamide, flutamide, nilutamide, leflunomide, teriflunomide and ailanthone. Lipophilicity is an important physicochemical [...] Read more.

The aim of this work was the use of both cluster analysis (CA) and Principal Component Analysis (PCA) for the evaluation of the lipophilicity of selected antiandrogen drugs such as abiraterone, bicalutamide, flutamide, nilutamide, leflunomide, teriflunomide and ailanthone. Lipophilicity is an important physicochemical parameter that is useful in determining the ADMET properties (absorption, distribution, metabolism, elimination and toxicity) of organic compounds that are being considered as potential drugs or drug candidates. Therefore, there is an urgent need to develop rapid, economical and efficient tools like theoretical methods that include CA and PCA analyses for the evaluation of the lipophilic properties of different bioactive compounds such as antiandrogens. In this study, we used both methods for comparison of the physicochemical properties (including lipophilicity) of seven antiandrogens with differ chemical structures. The lipophilicity parameters of the studied compounds were obtained in the form of R_MW by using a thin-layer chromatographic method (RP-TLC) under different conditions (i.e., various mobile phases composed of ethanol-water, propan-2-ol-water and acetonitrile-water and chromatographic plates RP2F₂₅₄, RP18F₂₅₄ and RP18WF₂₅₄), as well as logP values predicted using calculation methods (AlogPs, AClogP, AlogP, MlogP, xlogP2 and xlogP3). The CA and PCA analyses allowed the comparison of the examined compounds based on their lipophilicity parameters determined using RP-TLC and calculated logP values. Our study confirms the utility of both statistical methods (i.e., CA and PCA) to evaluate the lipophilicity of bioactive compounds belonging to the class of antiandrogen drugs. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 195 KiB

Open AccessAbstract

Pyridazin-3(2H)-one as New FABP4 Inhibitors Suggested by Molecular Growing Experiments

by Giuseppe Floresta, Letizia Crocetti, Chiara Zagni and Agostino Cilibrizzi

Med. Sci. Forum 2022, 14(1), 19; https://doi.org/10.3390/ECMC2022-13445 - 1 Nov 2022

Viewed by 608

Abstract

The therapeutic potential of fatty acid binding protein 4 (FABP4) is widely acknowledged. Currently, there are numerous clinical studies that indicate how fatty acid binding protein 4 inhibitors could be useful in the treatment of various diseases. To identify new and more potent [...] Read more.

The therapeutic potential of fatty acid binding protein 4 (FABP4) is widely acknowledged. Currently, there are numerous clinical studies that indicate how fatty acid binding protein 4 inhibitors could be useful in the treatment of various diseases. To identify new and more potent inhibitors, we utilized a two-step computational approach to design novel structures. Through the use of this approach, we were able to identify a new class of FABP4 inhibitors (FABP4i IC50 2.97 to 23.18 µM) that are capable of inhibiting the activity of FABP4 as low as Arachidonic acid (FABP4i IC50 3.42 ± 0.54 µM). In this study, we present the detailed structural and biological evaluation, and the synthetic procedures of the new pyridazinone-based scaffold FABP4i. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 233 KiB

Open AccessAbstract

Effect of Santolina chamaecyparissus on Physiological Parameters: Data from an Animal Model of Mammary Cancer

by Tiago Azevedo, Jessica Silva, Abigaël Valada, Lara Anjos, Ana Cristina Silvestre-Ferreira, Tiane Cristine Finimundy, Lillian Barros, Manuela Matos, Maria João Neuparth, Maria João Pires and Paula A. Oliveira

Med. Sci. Forum 2022, 14(1), 20; https://doi.org/10.3390/ECMC2022-13441 - 1 Nov 2022

Viewed by 858

Abstract

Breast cancer is the most common cancer worldwide. Santolina chamaecyparissus L. has successfully inhibited the MCF-7 cancer cell line. This study aims to evaluate the chemopreventive effects of S. chamaecyparissus aqueous extract (SCE) on female rats’ physiological parameters with mammary cancer induced by [...] Read more.

Breast cancer is the most common cancer worldwide. Santolina chamaecyparissus L. has successfully inhibited the MCF-7 cancer cell line. This study aims to evaluate the chemopreventive effects of S. chamaecyparissus aqueous extract (SCE) on female rats’ physiological parameters with mammary cancer induced by N-methyl-N-nitrosourea (MNU). The institutional ethics committee approved this study. Twenty-eight four-week-old female Wistar rats were divided into Control, MNU-induced (IND), SCE and SCE+IND. SCE was supplemented with drinking water (120 µg/mL). At 50 days of age, MNU was intraperitoneally administered. Humane endpoints were evaluated weekly. After twenty-one weeks, animals were sacrificed by ketamine/xylazine overdose and blood was collected. A complete blood count was performed using an automated haematology analyser. An autoanalyzer was used to measure serum markers (albumin, cholesterol, glucose and triglycerides). SCE’s chemical characterisation was performed by LC-MS, as it found nineteen phenolic compounds, the main molecules were myricetin-O-glucuronide and 1,3-O-dicaffeoylquinic acid. Regarding haemoglobin concentration, there was a difference (p = 0.050) between SCE and Control (16.38 ± 0.41 g/dL and 15.18 ± 0.29 g/dL, respectively). Mean Platelet Volume differed between SCE+IND (8.29 ± 0.15 fL) and IND (9.03 ± 0.26 fL) (p = 0.014). Platelet Distribution Width differed between 9.06 ± 0.14 fL (SCE + IND) and 10.58 ± 0.42 fL (IND) (p < 0.001), but also between SCE (8.78 ± 0.16 fL) and SCE + IND versus control (9.86 ± 0.17 fL) (p = 0.007 and p = 0.034, respectively). SCE had no effect on the humane endpoints or serum markers. Platelet size appears to have been significantly affected by SCE. SCE supplementation had no effect on liver or kidney function or the well-being of the animals, implying it could be a viable treatment option for breast cancer. Histological analysis will help confirm SCE’s toxicological profile. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 153 KiB

Open AccessAbstract

Genetically Encoded Photosensitizer Targeted to Methylated DNA

by Anastasiia Gorshkova, Dmitry Gorbachev, Mariia Moshareva, Lidiya Putlyaeva and Konstantin Lukyanov

Med. Sci. Forum 2022, 14(1), 21; https://doi.org/10.3390/ECMC2022-13654 - 16 Nov 2022

Viewed by 1240

Abstract

Genetically encoded photosensitizers are widely used in fundamental research and translational medicine due to their ability to generate reactive oxygen species (ROS) after photosensitizing. Previously, it was shown in mice that red dimeric fluorescent protein KillerRed is a potential photosensitizer that can be [...] Read more.

Genetically encoded photosensitizers are widely used in fundamental research and translational medicine due to their ability to generate reactive oxygen species (ROS) after photosensitizing. Previously, it was shown in mice that red dimeric fluorescent protein KillerRed is a potential photosensitizer that can be used for photodynamic therapy of cancer. In addition, it was demonstrated that HeLa cells expressing KillerRed fused to histone H2B cease proliferation upon illumination. A DNA repair protein, X-ray repair cross-complementing protein 1 (XRCC1), redistributed in the cell nuclei, indicating that the mechanism of phototoxic action of the construct involved DNA breaks generation. Here, we have constructed and tested a new genetically encoded photosensitizer molecule which introduces DNA breaks and activates the repair system in cancer-derived and embryonic cell lines more efficiently than previously described. The molecule consists of two parts: a SuperNova2 (monomeric mutant of KillerRed with enhanced phototoxicity) and methyl-CpG binding protein MECP2. The complex activates XRCC1 redistribution after illumination with lower power compared to the previously used construct. We suppose it can be explained by the tighter contact between photosensitizer and DNA. In addition, we hypothesize that the system should be error-prone for the expressed genes as it is targeted to the DNA which is silenced by methylation. Taking everything into consideration, the new genetically encoded construct has shown the improved ability to generate DNA breaks in the cancer cell lines. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 183 KiB

Open AccessAbstract

Forced Degradation Studies on Agents of Therapeutic Interest

by Nikita Pravin Pise, Arati Prabhu and Radhika Raheja

Med. Sci. Forum 2022, 14(1), 22; https://doi.org/10.3390/ECMC2022-13233 - 1 Nov 2022

Viewed by 685

Abstract

Chalcones possessing potential anti-Alzheimer’s activity were synthesised in our lab using the Claisen Schmidt reaction. FDS (Forced degradation protocols) protocols in accordance with ICH (International Conference on Harmonization) guidelines were applied to three thiophene chalcones TC1, TC2, and TC3. The method was developed [...] Read more.

Chalcones possessing potential anti-Alzheimer’s activity were synthesised in our lab using the Claisen Schmidt reaction. FDS (Forced degradation protocols) protocols in accordance with ICH (International Conference on Harmonization) guidelines were applied to three thiophene chalcones TC1, TC2, and TC3. The method was developed using Thermo Scientific C18 column (Agilent Technologies India Ltd., Mumbai, India 250 × 4.6 mm, 5 µm) as stationary phase and sodium acetate buffer (pH 3.0), with acetonitrile (40:60, v/v; 40:60, v/v; 25:75, v/v, respectively) as the mobile phase at 1 mL/min flow rate and 280 nm as detection wavelength. The developed method was successful in resolving TC1, TC2 and TC3 from its degradation products. TC1, TC2 and TC3 were eluted at a retention time of 10.5 min, 27.4 min and 10.2 min, respectively. HPLC (High Performance Liquid Chromatography) method was developed and validated for the individual untreated molecules and was found to be specific, selective, precise, reproducible, robust and linear in the range of about 5–15 ppm of the working standard concentration. The chalcones were stable under thermal and thermal-humidity stress, but degraded to different extents under acid-and base-catalysed hydrolysis, oxidative stress and photolytic conditions, as seen by HPLC analysis. The degradation of TC1 was studied by LC-MS and predictions of the mechanism of degradation were attempted. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 155 KiB

Open AccessAbstract

Synthesis of Azetidine-Based Beta-Amino Alcohols

by Linda Supe

Med. Sci. Forum 2022, 14(1), 23; https://doi.org/10.3390/ECMC2022-13471 - 1 Nov 2022

Viewed by 647

Abstract

Beta-amino alcohols are versatile chemicals used as scaffolds in medicinal chemistry and they are key factors for the efficacy of numerous pharmaceutical products. Locking the conformation of the active fragment in bioactive molecules may increase the potency and selectivity towards target receptors. Small [...] Read more.

Beta-amino alcohols are versatile chemicals used as scaffolds in medicinal chemistry and they are key factors for the efficacy of numerous pharmaceutical products. Locking the conformation of the active fragment in bioactive molecules may increase the potency and selectivity towards target receptors. Small rings, especially the azetidine framework, can serve as conformational lock yet providing the necessary size for receptor binding. Herein, we report the synthesis of enantiopure beta-amino alcohols where the motif is combined with a structurally constrained azetidine cycle. The key steps towards target molecules include base-induced azetidine ring closure and subsequent beta-amino alcohol core installation. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 193 KiB

Open AccessAbstract

Synthesis, Molecular Docking Analysis, ADMET and Drug Likeness Prediction of a Benzenesulfonamide Derivative Analogue of SLC-0111

by Yousra Ouafa Bouone, Abdeslem Bouzina and Nour-Eddine Aouf

Med. Sci. Forum 2022, 14(1), 24; https://doi.org/10.3390/ECMC2022-13407 - 1 Nov 2022

Cited by 1 | Viewed by 911

Abstract

Carbonic anhydrases are metalloenzymes that regulate the interconversion of CO₂ and H₂CO₃, a reaction involved in many physiological processes. A disfunction of these enzymes is known to induce many diseases such as glaucoma, epilepsy and cancer. As a [...] Read more.

Carbonic anhydrases are metalloenzymes that regulate the interconversion of CO₂ and H₂CO₃, a reaction involved in many physiological processes. A disfunction of these enzymes is known to induce many diseases such as glaucoma, epilepsy and cancer. As a result, there is a need to design new target molecules with inhibitory effects on carbonic anhydrases (CAs). The most well-known compounds that inhibit CAs are sulfonamide-containing molecules, including valdecoxib, acetazolamide and the antitumor agent recently introduced to phase II clinical trials: the SLC-0111. With an intention to obtain a new potential drug candidate, an analogue of the SLC-0111 compound was designed and synthesized using sulfanilamide, chlorosulfonyl isocyanate and aniline. IR (infrared), NMR (nuclear magnetic resonance) spectroscopy and EA (elemental analysis) were used in the characterization of the structure. In order to explore the potentiality of our newly synthesized product to inhibit Cas, a docking simulation was performed on the binding pockets of both carbonic anhydrase II complexed with valdecoxib (pdb: 2AW1) and carbonic anhydrase IX complexed with SLC-0111 (pdb: 5JN3). The new derivative revealed an interesting stability inside the cavities of CA II and CA IX with docking scores of −9.782 and −7.466, respectively, and showed an efficient binding affinity in both cases through the formation of metal coordination with Zn and a hydrogen bond with the Thr199, which is known to be essential for the inhibition. Other significant extra interactions were also observed with other residues in isoform II. Further, the pharmacokinetics properties and drug likeness were predicted using in silico tools: SwissADME and MolSoft online servers. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 206 KiB

Open AccessAbstract

Coelenterazine Derivatives as Potential Drugs for Photodynamic Therapy

by Daiane Nascimento Maronde, Ivo E. Sampaio-Dias, Luís Pinto da Silva, Leandro M. O. Lourenço and José E. Rodríguez-Borges

Med. Sci. Forum 2022, 14(1), 25; https://doi.org/10.3390/ECMC2022-13447 - 1 Nov 2022

Viewed by 716

Abstract

Cancer is one of the main leading causes of death worldwide, and its treatment is highly complex and known to cause serious side effects for patients. Photodynamic therapy (PDT) has gained a worldwide impact as a promising alternative strategy to overcome or minimize [...] Read more.

Cancer is one of the main leading causes of death worldwide, and its treatment is highly complex and known to cause serious side effects for patients. Photodynamic therapy (PDT) has gained a worldwide impact as a promising alternative strategy to overcome or minimize these potential side effects observed in conventional therapeutical approaches. This therapy is a minimally invasive treatment that combines a photosensitizer (PS), visible light, and molecular oxygen (³O₂). When excited, the PS interacts with ³O₂ to generate reactive oxygen species (ROS), mainly as singlet oxygen (¹O₂) which, in turn, induces cytotoxic effects in cancer cells. In a recent study led by our research group, coelenterazine (Clz) analogues have shown relevant cell-selective toxicity in different cancer cell lines, such as breast, liver, prostate, and neuroblastoma, without cytotoxic effects in the corresponding non-tumoral cells. Based on these results, this work aims to synthesize a new series of Clz-inspired PS derived from pyrazine scaffold, a common precursor for the synthesis of Clz and its structure-related analogues. Herein, we describe some methodological approaches for the synthesis of pyrazine-based precursors with high chemical yields and their chemical characterization for the assembly of Clz analogues. Currently, these compounds are being studied for the assembly of new PS with potential application for PDT. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 186 KiB

Open AccessAbstract

Magnetic Nanoparticles Conjugated to Amylovis^® as Contrast Agents, Synthesis and In Silico Evaluation

by Claudia González, Alicia Díaz, Marquiza Sablón and Chryslaine Rodríguez

Med. Sci. Forum 2022, 14(1), 26; https://doi.org/10.3390/ECMC2022-13443 - 1 Nov 2022

Viewed by 691

Abstract

Iron oxide nanoparticles (IONPs) have high relativity for Magnetic Resonance Imaging (MRI) and have shown a long half-life which can covalently bind with drugs and antibodies that can be used for increased contrast while imaging with MRI. IONPs are approved by the U.S [...] Read more.

Iron oxide nanoparticles (IONPs) have high relativity for Magnetic Resonance Imaging (MRI) and have shown a long half-life which can covalently bind with drugs and antibodies that can be used for increased contrast while imaging with MRI. IONPs are approved by the U.S Food and Drug Administration to be used as a contrast agent for MRI in vivo. The Cuban Neuroscience Center has developed a new family of naphthalene derivative compounds called Amylovis^® to be used to diagnose and treatment of Alzheimer’s disease (AD). The goal of this work is to synthesize IONPs with different coatings to be conjugated to Amylovis^® as contrast agents for MRI. Coprecipitation method was employed to obtain the magnetic nuclei, and two synthesis methodologies were performed to coat the IONPs (post-synthesis or in situ). The different coatings used were the following: (3-aminopropyl)triethoxysilane (APTES), dicarboxylic polyethyleneglycol, galic acid, polyacrylic acid and citrate. Carbodiimide method was used as synthetic protocol to conjugate the Amylovis^® moiety to different coatings. The nanoparticles were characterized by DRX, FT-IR, Electrophoretic Light Scattering (ELS) and Dynamic Light Scattering (DLS). Moreover, the stability of nanoparticles in water was evaluated using a sedimentation curve. In order to determine the potential interaction of nanosystems with the beta amyloid peptides, a molecular docking was carried out. The theoretical study showed that coatings do not affect the interaction of Amylovis^® with the receptor, and the new polar groups incorporated increased the affinity to receptor. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 206 KiB

Open AccessAbstract

In Vitro Inhibitory Effects on Pancreatic Lipase and α-Glucosidase Activity by Extracts and Fractions of Lavandula angustifolia L. from Southern Italy

by Rosa Tundis, Anna R. Cappello and Monica R. Loizzo

Med. Sci. Forum 2022, 14(1), 27; https://doi.org/10.3390/ECMC2022-12874 - 18 Aug 2022

Viewed by 585

Abstract

Lavandula angustifolia is one of the most popular medicinal plants, and is a rich source of bioactive compounds. Most of the studies on lavender have focused on its essential oil and its use as a sleep aid, calmative, fragrant, insect repellant and flavoring [...] Read more.

Lavandula angustifolia is one of the most popular medicinal plants, and is a rich source of bioactive compounds. Most of the studies on lavender have focused on its essential oil and its use as a sleep aid, calmative, fragrant, insect repellant and flavoring agent. This work is aimed at investigating, for the first time, the potential role of L. angustifolia in the management of metabolic syndrome (MetS), one of the major and escalating public-health and clinical challenges worldwide. Herein, the aerial parts of L. angustifolia, collected in June 2021 in the “Parco Nazionale del Pollino”, Southern Italy, were subjected to extraction by maceration with ethanol. Then, the total extract was partitioned with solvents at different polarities such as n-hexane, dichloromethane and ethyl acetate. The extract and fractions were evaluated for their ability to inhibit alpha-glucosidase as well as lipase. The ethanol extract remarkably inhibited α-glucosidase and lipase (IC₅₀ of 2.55 and 30.50 μg/mL, respectively) better than the positive control acarbose and orlistat (IC₅₀ of 35.51 and 37.12 μg/mL, respectively). The most active fraction was dichloromethane with an IC₅₀ of 14.67 and 17.64 μg/mL, against α-glucosidase and lipase, respectively. Taking into account the obtained results, L. angustifolia could be used for the formulation of new products; however, further preclinical studies will be needed to confirm its in vivo efficacy, as well as to prove the safety of the tested extracts and fractions. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 169 KiB

Open AccessAbstract

Molecular Docking Analysis of Novel Thiourea Derivatives of Naproxen with Potential Anti-Inflammatory Activity

by Nikola Nedeljković, Vladimir Dobričić, Marina Mijajlović, Zorica Vujić and Miloš Nikolić

Med. Sci. Forum 2022, 14(1), 28; https://doi.org/10.3390/ECMC2022-13279 - 1 Nov 2022

Viewed by 799

Abstract

Administration of current non-steroidal anti-inflammatory drugs is often associated with serious adverse effects. Therefore, there is a constant need to develop new molecules with anti-inflammatory activity. On the other hand, thiourea derivatives of non-steroidal anti-inflammatory drugs demonstrated significant anti-inflammatory activity in numerous studies. [...] Read more.

Administration of current non-steroidal anti-inflammatory drugs is often associated with serious adverse effects. Therefore, there is a constant need to develop new molecules with anti-inflammatory activity. On the other hand, thiourea derivatives of non-steroidal anti-inflammatory drugs demonstrated significant anti-inflammatory activity in numerous studies. To clarify anti-inflammatory mechanism of action, in silico study was performed on four thiourea derivatives of naproxen, which were selected from the initial group of compounds synthesized by our research group. Tested compounds contain p-fluoroaniline (16), p-methoxyaniline (17), p-ethoxyaniline (18) and aniline (19) in the side chains. Selected 3D structures of enzymes COX-2 (3NT1) and 5-LOX (6NCF) were taken from PDB database. MAKE Receptor 3.2.0.2 software (OpenEye Scientific Software, Inc, Santa Fe, NM, United States) was used for preparation of enzymes’ active sites, while ligands were prepared in OMEGA 2.5.1.4. FRED 3.2.0.2 software (OpenEye Scientific Software, Inc, Santa Fe, NM, United States) was employed for the analysis of binding poses into enzymes’ active sites. All tested compounds showed key binding interactions with both enzymes. The highest number of key binding interactions was observed during molecular fitting of derivative 19 into the active site of COX-2 and derivatives 16 and 18 into the 5-LOX. Derivative 17 had the lowest value of free binding energy for both target enzymes (−14.90 kcal/mol for COX-2 and −9.57 kcal/mol for 5-LOX). Therefore, all analyzed compounds represent potential dual inhibitors of mentioned enzymes. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 195 KiB

Open AccessAbstract

Selected Biomarkers of Inflammation in Patients with Head and Neck Cancer Depending on the Tumor Location

by Jarosław Nuszkiewicz, Marlena Budek, Jolanta Czuczejko and Karolina Szewczyk-Golec

Med. Sci. Forum 2022, 14(1), 29; https://doi.org/10.3390/ECMC2022-13297 - 1 Nov 2022

Viewed by 679

Abstract

Head and neck cancers (HNCs) are a group of neoplasms located in the area of the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity and salivary glands. HNCs are the sixth most common type of cancer in the Europe population. As in other [...] Read more.

Head and neck cancers (HNCs) are a group of neoplasms located in the area of the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity and salivary glands. HNCs are the sixth most common type of cancer in the Europe population. As in other neoplastic diseases, chronic inflammation occurs in HNC, affecting not only the location of the tumor, but also distant healthy tissues. In patients with HNC, changes in the levels of pro- and anti-inflammatory cytokines are observed. The aim of this study was to assess the level of interleukin 3 (IL-3), IL-4, IL-13, monocyte chemoattractant protein 1 (MCP-1) and MCP-2 in patients with HNC depending on the tumor localization. The study group consisted of 40 HNC patients divided into two groups according to the localization of the tumor: 20 subjects with cancer located in the area of the oral cavity (OC) and 20 subjects with cancer located in the area of pharynx and larynx (PL). Blood serum samples were used to perform the analyses. A value of p < 0.05 was considered as statistically significant. In the PL group, statistically significant higher concentrations of IL-13 and MCP-1 were observed. The level of IL-13 in the OC group was 3.99 ± 0.50 pg/mL, while in the PL group it was 5.79 ± 0.64 pg/mL. The MCP-1 concentration was 68.15 ± 7.06 pg/mL and 109.01 ± 10.76 pg/mL, respectively. There were no statistically significant differences in the levels of IL-3, IL-4 and MCP-2. This experiment indicates that IL-13 and MCP-1 may be potential biomarkers differentiating tumor localization in patients with HNC. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 204 KiB

Open AccessAbstract

Effect of Preservative Solution Modified by the Addition of Magnesium and Manganese on the Nephron Functions of Isolated Perfused Porcine Kidneys

by Aneta Ostróżka-Cieślik, Barbara Dolińska and Florian Ryszka

Med. Sci. Forum 2022, 14(1), 30; https://doi.org/10.3390/ECMC2022-13301 - 1 Nov 2022

Viewed by 668

Abstract

We present another paper in a series of studies on the effectiveness of preservation solutions modified with bio-elements in protecting ischemic organs for transplantation. Bio-elements as components of organ perfusion and preservation solutions can potentially increase the efficiency of graft preservation. Macro- and [...] Read more.

We present another paper in a series of studies on the effectiveness of preservation solutions modified with bio-elements in protecting ischemic organs for transplantation. Bio-elements as components of organ perfusion and preservation solutions can potentially increase the efficiency of graft preservation. Macro- and micronutrients are involved in biochemical reactions and metabolic processes of the cell. Many of them exhibit antioxidant properties, protecting against oxidative damage. The aim of this study was to evaluate the effectiveness of manganese (Mn²⁺) and magnesium (Mg²⁺) as components of Biolasol solution. The study was conducted in a model of isolated porcine kidneys collected from Polish Large White pigs. Approval was obtained from II Local Ethics Committee Krakow: number 1046/2013. Kidneys were preserved through static cold storage (SCS) using Biolasol (control) and modified Biolasol (A: Mn²⁺/1 µg/L; B: Mg²⁺/1 µg/L and Mn²⁺/1 µg/L). Kidneys were flushed with solutions after 48 h of storage. Potassium, urea, and creatinine concentrations were highest in the Biolasol + Mn²⁺ group after 48 h storage ([K⁺]: up by 50% vs. Biolasol and 119% vs. Biolasol + Mn²⁺ + Mg²⁺; urea: up by 18% vs. Biolasol and 300% vs. Biolasol + Mn²⁺ + Mg²⁺; creatinine: up by 250% vs. Biolasol and 240% vs. Biolasol + Mn²⁺ + Mg²⁺; p < 0.05). Protein concentration was lowest in the Biolasol + Mn²⁺ + Mg²⁺ group (by 81% vs. Biolasol and 67% vs. Biolasol + Mn²⁺; p < 0.05). The simultaneous introduction of Mn²⁺ + Mg²⁺ ions into the Biolasol composition improved renal function indices. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 196 KiB

Open AccessAbstract

Microwave-Assisted Synthesis and Butyrylcholinesterase Inhibitory Activity of New Azobenzene Derivatives

by Martina Donozo, Valeria Cavallaro, Ana Paula Murray and Carlos Javier Baier

Med. Sci. Forum 2022, 14(1), 31; https://doi.org/10.3390/ECMC2022-13464 - 1 Nov 2022

Viewed by 626

Abstract

Cholinesterase inhibitors (ChEis) play an important role in enhancing cholinergic synaptic activity and, consequently, have therapeutic applications in the treatment of neurodegenerative diseases like Alzheimer’s disease (AD). The inhibition of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) avoids the degradation of the neurotransmitter [...] Read more.

Cholinesterase inhibitors (ChEis) play an important role in enhancing cholinergic synaptic activity and, consequently, have therapeutic applications in the treatment of neurodegenerative diseases like Alzheimer’s disease (AD). The inhibition of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) avoids the degradation of the neurotransmitter acetylcholine and constitutes a pharmacotherapeutic strategy that has shown important efficacy reducing AD symptoms. Based on previous results obtained by our group and with the purpose of obtaining diverse and more effective compounds, a series of new azobenzene derivatives were designed and synthesized. Additionally, considering the powerful AChE inhibition displayed by this type of compounds it was decided in this work to expand the research by testing BChE inhibitory activity. Nine azobenzene derivatives, with different spacer lengths (4–8 carbons) and terminal tertiary amines, were synthesized by microwave-assisted synthesis and tested for biological activity in vitro. The synthesis was carried out using a microwave oven (in two steps) with a reaction time of around 20 min and moderate to good yields. In addition, cytotoxic properties of the compounds in SH-SY5Y human neuroblastoma cells will be tested. The inhibitory activity of BChE was determined using Ellman’s method. All the compounds synthesized were active against BChE, the one with a six carbon atom spacer and ethylbenzylamine moiety (IC₅₀: 6.621 µM ± 0.001) being the most effective. From these results we could establish that the optimum length for the spacer was six carbons and that diamines were less active than monoamines. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 182 KiB

Open AccessAbstract

Coordination Compounds of Cu(II) and Ni(II) with 1-(Morpholin-4-yl)propane-1,2-dione 4-allylthiosemicarbazone: A Protection from Free Radical Damage

by Ianina Ulchina, Vasilii Graur, Olga Garbuz, Victor Tsapkov and Aurelian Gulea

Med. Sci. Forum 2022, 14(1), 32; https://doi.org/10.3390/ECMC2022-13252 - 1 Nov 2022

Viewed by 671

Abstract

Free radicals are highly reactive and unstable particles that are produced in the body during normal metabolic functions or by exposure to toxins in the environment, such as tobacco smoke and ultraviolet light. Free radicals have a lifespan of only a fraction of [...] Read more.

Free radicals are highly reactive and unstable particles that are produced in the body during normal metabolic functions or by exposure to toxins in the environment, such as tobacco smoke and ultraviolet light. Free radicals have a lifespan of only a fraction of a second, but during that time can damage DNA, sometimes resulting in mutations that can lead to various diseases, including heart disease and cancer. The antioxidants can neutralize unstable particles, reducing the risk of damage. So the design of new substances as a potent antioxidant is an actual problem in the modern world. For this purpose, it was synthesized coordination compounds of Cu(II) and Ni(II) with 1-(morpholin-4-yl)propane-1,2-dione 4-allylthiosemicarbazone (HL). HL was obtained by the condensation reaction between 1-(morpholin-4-yl)propane-1,2-dione and 4-allylthiosemicarbazide in an ethanol solution. Its structure and purity were proven using ¹H and ¹³C NMR spectroscopy. The coordination compounds were synthesized by the interaction of HL with metal salts in a 1:1 and 1:2 molar ratio. The composition of these compounds was determined using elemental analysis: Cu(L)X (X=Cl⁻, Br⁻, NO₃⁻), Ni(HL)₂(NO₃)_2, Ni(L)Cl. These complexes were studied by molar conductivity, IR spectra, and X-ray diffraction. The study of antioxidant activity by the ABTS^•+ method showed that the most active compound is Ni(HL)₂(NO₃)₂. Its IC₅₀ value toward ABTS^•+ is 19.6 µM, so it is 1.7 times more active than Trolox, a water-soluble antioxidant, which is used in medicine. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 195 KiB

Open AccessAbstract

Novel Copper(II) Complexes with S-Substituted Isothiosemicarbazone as Highly Selective Anticancer Compounds against BxPC-3 Cell Line

by Vasilii Graur, Irina Usataia, Olga Garbuz and Aurelian Gulea

Med. Sci. Forum 2022, 14(1), 33; https://doi.org/10.3390/ECMC2022-13253 - 1 Nov 2022

Viewed by 677

Abstract

Cancer is a major disease worldwide. Therefore, scientists are in a constant search for new, more effective and selective substances, not damaging normal cells, for the treatment of this disease. The use of coordination compounds such as anticancer agents is based on the [...] Read more.

Cancer is a major disease worldwide. Therefore, scientists are in a constant search for new, more effective and selective substances, not damaging normal cells, for the treatment of this disease. The use of coordination compounds such as anticancer agents is based on the interaction between DNA and metal-based complexes. It is known that thiosemicarbazones, isothiosemicarbazones, and 3d metal complexes with them often exhibit high anticancer activity. In this work, the S-methyl group in the composition of 2-acetylpyridine 4-allyl-S-methylisothiosemicarbazone (HL¹) was replaced by an S-allyl group. As a result, 2-acetylpyridine 4,S-diallylisothiosemicarbazone (HL²) was obtained. Two novel copper(II) coordination compounds were synthesized with HL²: Cu(HL²)Cl₂ and Cu(HL²)Br₂. The inhibitory activity of these novel coordination compounds was tested and compared with the corresponding activities of previously described complexes with 2-acetylpyridine 4-allyl-S-methylisothiosemicarbazone. The inhibitory activity toward the normal MDCK cell line decreased. Their IC₅₀ values are in the range of 1.2–1.4 μM, while the corresponding complexes with HL¹ have IC₅₀ values of 0.35–1.0 μM. Therefore, the novel complexes have a lower impact on normal cells. At the same time, the inhibitory activity toward the human pancreatic cancer cell line (BxPC-3) increased 2.5–18 times. The IC₅₀ values of the novel complexes toward BxPC-3 cells are in the range of 5–8 nM. This means that the selectivity indexes (the ratio between IC₅₀ values of normal cells and cancer cells) of the novel complexes are in the range of 150–280, which is very promising for further study of these complexes as potent selective anticancer drugs. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 180 KiB

Open AccessAbstract

In Silico Approaches to Evaluate the Binding Affinity of Verbascoside on Sirtuin1 (SIRT1) Receptor for the Treatment of Diabetic Wound Healing

by Ankit Majie, Rajdeep Saha, Shlok Kumar, Riya Aryan and Biswatrish Sarkar

Med. Sci. Forum 2022, 14(1), 34; https://doi.org/10.3390/ECMC2022-13286 - 1 Nov 2022

Viewed by 1044

Abstract

Diabetes mellitus is one of the leading metabolic disorders which leads to chronic wounds of the lower limbs. Complications such as abnormal vasculopathy and functioning of endothelial cells, decreased glucose-6-phosphate dehydrogenase, inadequate remodeling of extracellular matrix, decreased nitric oxide synthase, neuropathy, and secondary [...] Read more.

Diabetes mellitus is one of the leading metabolic disorders which leads to chronic wounds of the lower limbs. Complications such as abnormal vasculopathy and functioning of endothelial cells, decreased glucose-6-phosphate dehydrogenase, inadequate remodeling of extracellular matrix, decreased nitric oxide synthase, neuropathy, and secondary infections delay the process of wound healing, which finally leads to amputation of the lower extremities. In vitro and in vivo studies exploring the role of the SIRT1 receptor in diabetic wounds have shown decreased expression of the receptor along with an increase in the levels of reactive oxygen species (ROS). Treatment with specific SIRT1 agonists in animal models has demonstrated an increase in angiogenesis and a faster rate of wound healing. Verbascoside has a potential role in wound healing by proliferation and keratinocyte migration, synthesis of extracellular matrix, increasing neutrophil and macrophage function, and increasing angiogenesis. Thus, a molecular docking study was conducted to evaluate the interaction between Verbascoside and the SIRT1 receptor (PDB ID: 4ZZJ). The least binding energy was found to be −9.6 kcal/mol, which suggested a high binding interaction between the receptor and the ligand. The interacting amino acids include ARG274, GLU467, PRO468, LEU469, PRO470, PHE474, GLU477, ARG649, and VAL657, which is the common binding pocket for polyphenols. However, in vitro and in vivo studies are required to further evaluate the activity of verbascoside in diabetic wound healing. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 186 KiB

Open AccessAbstract

Synthesis of 4-acetamido-octahydrochromene Derivatives Based on (–)-Isopulegol—Promising Analgesic Agents

by Nikolai Li-Zhulanov, Valeriya Kuznetsova, Konstantin Volcho and Mihail Khvostov

Med. Sci. Forum 2022, 14(1), 35; https://doi.org/10.3390/ECMC2022-13498 - 7 Nov 2022

Viewed by 1110

Abstract

Selective modification of natural compounds is one of the most important ways to develop and search for new biologically active substances of various structural types. It was found earlier that some compounds with octahydro-2H-chromene scaffolds synthesized from monoterpenoid (–)-isopulegol demonstrated promising [...] Read more.

Selective modification of natural compounds is one of the most important ways to develop and search for new biologically active substances of various structural types. It was found earlier that some compounds with octahydro-2H-chromene scaffolds synthesized from monoterpenoid (–)-isopulegol demonstrated promising biological activity, e.g., analgesic, and antiviral activities, inhibitory activity against DNA repair enzyme Tdp1. The flexible method for the synthesis of octahydro-2H-chromenes derivatives is the Prins cyclization. This reaction could serve also as an initiator of a three-component tandem reaction. For example, the sequence of the Prins and Ritter reactions is one of the best synthetic methods to efficiently build six-membered fragment of 4-amidotetrahydropyran in a one-pot single step reaction. In this work we have developed a method for synthesis of chiral 4-acetamido-octahydro-2H-chromenes. We used tandem Prins-Ritter reaction between (–)-isopulegol and a set of ketones in acetonitrile. Desired products were formed as a mixture of 4R/4S diastereomers, where 4S one is a major isomer. Development of new analgesic agents with high activity and low toxicity is important task. It is known that the heterocyclic compounds synthesized from (–)-isopulegol exhibit analgesic activity. In the study of the analgesic activity of the synthesized compounds in vivo, we found that a number of derivatives showed high analgesic activity reliably and not inferior in efficiency to the reference drug sodium diclofenac administered at a similar dose. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 172 KiB

Open AccessAbstract

Screening of Urea Transporter Inhibitors in Celery Seeds by UPLC-TOF-MS

by Guanzhong Chen, Wei Wei, Nan Xiang, Xinhui Pan and Xiaoda Yang

Med. Sci. Forum 2022, 14(1), 36; https://doi.org/10.3390/ECMC2022-13278 - 1 Nov 2022

Viewed by 672

Abstract

Urea transporters (UTs) are a kind of transmembrane protein that specifically permeate urea, and play an important role in the mechanism of urine concentration. Selective knockout of UT can concentrate urea without affecting water and electrolytes, resulting in selective diuresis, which is a [...] Read more.

Urea transporters (UTs) are a kind of transmembrane protein that specifically permeate urea, and play an important role in the mechanism of urine concentration. Selective knockout of UT can concentrate urea without affecting water and electrolytes, resulting in selective diuresis, which is a promising new diuretic target. Most of the currently reported UT inhibitors are obtained from small molecular libraries screened. We subjected the methanolic extract of celery seed to silica gel column chromatography analysis, and screened the column chromatographic fractions of celery seed for UT-B inhibitory activity using the reported erythrocyte lysis model. The UT-B inhibitory activity was also screened for the fractions of celery seed separated by column chromatography, using the reported erythrocyte lysis model. The chemical composition of the active site was identified using UPLC-TOF-MS, and the active compounds were selected in combination with molecular docking and ADMET prediction. Screening of the extracted parts of celery seed, using an erythrocyte lysis model, yielded nine small molecules with good inhibitory activity, namely esters, phenols, and organic acids. This experiment shows that compounds with UT-B inhibitory effects can be found in ethnic medicinal materials, which not only provides new ideas for the discovery of UT-B inhibitors, but also contributes to the development of ethnic medicines. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 211 KiB

Open AccessAbstract

Chemiluminescent Self-Activating Photosensitizers for Selective Anticancer Therapy

by Carla M. Magalhães, Patricia González-Berdullas, Joaquim C. G. Esteves da Silva and Luís Pinto da Silva

Med. Sci. Forum 2022, 14(1), 37; https://doi.org/10.3390/ECMC2022-13174 - 1 Nov 2022

Viewed by 627

Abstract

Cancer is a challenging disease to treat, regarding treatment efficiency and side-effects [...] Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 176 KiB

Open AccessAbstract

Evaluation of Cytotoxic Activity of Small Aminated Quinolinequinones In Vitro as Anti-Cancer Molecules

by Ayse Tarbin Jannuzzi, Ayse Mine Yilmaz Goler and Amac Fatih Tuyun

Med. Sci. Forum 2022, 14(1), 38; https://doi.org/10.3390/ECMC2022-13206 - 1 Nov 2022

Viewed by 791

Abstract

Quinolinequinones, which are bicyclic heterocycles and quinone derivatives due to their broad range of biological activities, which include strong antifungal, antibacterial, antimalarial, and anticancer, have long been the subject of numerous investigations. After successful synthesis and characterization of aminated quinolinequinones (AQQ) and antimicrobial [...] Read more.

Quinolinequinones, which are bicyclic heterocycles and quinone derivatives due to their broad range of biological activities, which include strong antifungal, antibacterial, antimalarial, and anticancer, have long been the subject of numerous investigations. After successful synthesis and characterization of aminated quinolinequinones (AQQ) and antimicrobial evaluation by our group, compounds were subjected to the NCI-60 Human Tumor Cell Lines Screen to determine anticancer activity. According to the NCI report, we further investigated the cytotoxic effects of selected compounds, AQQ6 and AQQ9, on the growth of DU-145 prostate cancer, MDA-MB-231 breast cancer, and HCT-116 colon cancer lines after 24 h treatment by MTT assay at 1–100 μM concentrations. HUVEC human umbilical vein endothelial cells were used as a non-cancerous cell line to determine the cancer selectivity of the compounds. Doxorubicin was used as a positive control drug. AQQ6 was more cytotoxic than AQQ9 and showed good cytotoxicity against DU-145 prostate cancer cells. Then, molecular pathways related to the cytotoxic effects of AQQ6 were investigated with analysis of cell cycle distribution, measurements of cellular ROS levels, and apoptosis/necrosis rate with flow cytometry at 1, 2.5, and 5 μM AQQ6 concentrations. According to our findings, AQQ6 induces G0/G1 cell cycle arrest dose-dependently. Additionally, apoptotic and necrotic cell populations significantly increased with 2.5 and 5 μM AQQ6 concentrations. AQQ6 did not affect cellular ROS levels. In conclusion, AQQ6 shows antiproliferative effects against DU-145 prostate cancer cells, which are mediated through cell cycle arrest and apoptotic and necrotic cell death. Potentially, AQQ6 can be a promising drug candidate for further anticancer research. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 190 KiB

Open AccessAbstract

Assessment of the Relationship between Selected Parameters of Inflammation in Patients with Neuroendocrine Neoplasms

by Marlena Budek, Jarosław Nuszkiewicz, Jolanta Czuczejko and Karolina Szewczyk-Golec

Med. Sci. Forum 2022, 14(1), 39; https://doi.org/10.3390/ECMC2022-13298 - 1 Nov 2022

Viewed by 804

Abstract

Neuroendocrine tumors (NENs) originate from neuroendocrine cells located in a wide variety of organ systems. Gastrointestinal-pancreatic tumors (GEP-NETs) constitute the largest group (approximately 70%). NENs are heterogeneous in terms of location, malignancy potential, prognosis, treatment methods and functionality, which often makes their diagnosis [...] Read more.

Neuroendocrine tumors (NENs) originate from neuroendocrine cells located in a wide variety of organ systems. Gastrointestinal-pancreatic tumors (GEP-NETs) constitute the largest group (approximately 70%). NENs are heterogeneous in terms of location, malignancy potential, prognosis, treatment methods and functionality, which often makes their diagnosis difficult. The accumulating evidence points to the role of inflammatory factors in the GEP-NETs microenvironment. The aim of the study was to determine the concentrations of interferon gamma (IFN-γ), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and interleukin 10 (IL-10) in patients with GEP-NETs. The study included 63 patients of the Prof. F. Łukaszczyk Oncology Center in Bydgoszcz with a diagnosis of neuroendocrine neoplasms of the gastrointestinal tract (GT, n = 42) and pancreas (PA, n = 21). The concentration of cytokines was measured by the enzyme immunoassay method using ready-made ELISA kits. A statistical analysis was performed and p < 0.05 was considered as statistically significant. The results were presented as the mean value and the standard error. The levels of IFN-γ, IL-6 and MCP-1 were statistically higher in the PA group than in the patients with GT-NENs. The concentration of IL-10, which is a factor inhibiting cytokine synthesis, did not show a significant difference between the GT and PA groups. Increased levels of inflammation in pancreatic NENs, compared to gastrointestinal NENs, have been observed. It has been noted that the disturbed balance between pro-inflammatory and anti-inflammatory factors may play a role in the development of neuroendocrine tumors. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 172 KiB

Open AccessAbstract

Identification of Novel ERβ Ligands

by Sofija S. Bekić, Andrea R. Nikolić, Marija N. Sakač, Edward T. Petri and Anđelka S. Ćelić

Med. Sci. Forum 2022, 14(1), 40; https://doi.org/10.3390/ECMC2022-13154 - 1 Nov 2022

Viewed by 709

Abstract

The estrogen receptor (ER) is a major therapeutic target in treating estrogen-related diseases, such as breast cancer. There is a need to develop potent ER ligands capable of selectively targeting cancer cells without affecting normal cells. Blocking ERα action by antagonists and inhibiting [...] Read more.

The estrogen receptor (ER) is a major therapeutic target in treating estrogen-related diseases, such as breast cancer. There is a need to develop potent ER ligands capable of selectively targeting cancer cells without affecting normal cells. Blocking ERα action by antagonists and inhibiting steroidogenic enzymes has been standard therapy in breast cancer treatment for many years. On the other hand, the ERβ isoform usually has antiproliferative and tumor-suppressive functions, so targeting ERβ with specific agonists represents a promising new approach not only in breast cancer but also in prostate cancer therapy. Besides the anticancer activity of ERβ agonists, their application is considered in treating depression, anxiety, and inflammation. To obtain potent antiproliferative agents, a triazole ring is often incorporated as a pharmacophore in the steroid skeleton. This study evaluates the binding affinity of novel N(2)-substituted D-condensed steroidal triazoles for ligand-binding domains (LBDs) of ERβ and androgen receptors using a yeast-based fluorescent assay. The LBD of the steroid receptor was expressed in-frame with a yellow fluorescent protein (YFP) in Saccharomyces cerevisiae. Upon ligand-binding induced dimerization, fluorescence resonance energy transfer (FRET) between YFP molecules was analyzed using fluorescence spectroscopy and microscopy. We identified new selective ERβ ligands without androgenic properties, but further experiments are required to determine whether their mechanism of action is agonistic or antagonistic. Considering the broad therapeutic potential of specific ERβ ligands, our findings indicate that steroid derivatives containing triazole are promising bioactive compounds in the field of anticancer agents. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 176 KiB

Open AccessAbstract

β-Cyclodextrin Nanosponges for Oral Drug Delivery of Anti-Hypertensive Drug

by Ritika Prashant Khivansara, Sandhya Bajirao Jadhav, Varsha Daund and Atul Sherje

Med. Sci. Forum 2022, 14(1), 41; https://doi.org/10.3390/ECMC2022-13240 - 1 Nov 2022

Viewed by 817

Abstract

Nicardipine (NC) is an antihypertensive drug indicated for treatment of high blood pressure and angina. It belongs to BCS class-II, having poor solubility and low oral bioavailability. The present work was aimed at developing pyromellitic dianhydride (PMDA) cross-linked β-cyclodextrin (βCD) nanosponges (NS) for [...] Read more.

Nicardipine (NC) is an antihypertensive drug indicated for treatment of high blood pressure and angina. It belongs to BCS class-II, having poor solubility and low oral bioavailability. The present work was aimed at developing pyromellitic dianhydride (PMDA) cross-linked β-cyclodextrin (βCD) nanosponges (NS) for improved solubility and drug release. The βCDNS were prepared by the solvent evaporation method in 1:2, 1:4, 1:6 w/w ratio of β-CD: PMDA. The prepared drug loaded β-CDNS were subjected to characterization studies such as DSC, FESEM, FTIR, PXRD and particle size. Characterisation studies confirmed the formation of nanosponges and the entrapment of drug molecules into them. The βCDNS prepared in 1:4 w/w ratio of βCD: PMDA showed the highest increase in solubility and entrapment efficiency, with particle size of 411 nm and −20.9 mV zeta potential. The molecular docking study revealed the formation of stable complexes through interaction of NC and βCD. The nanosponges were formulated into a capsule dosage form by blending the drug-loaded nanosponges with granulated excipients such as talc, aerosol, lactose and starch. The powder blend showed acceptable flow properties. The in vitro dissolution studies of the optimized capsule formulation, performed using USP Type-I apparatus, showed considerably higher drug release compared to pure NC. Thus, PMDA cross-linked βCDNS represents a novel approach to solubility enhancement and an improved dissolution of the selected model drug. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 187 KiB

Open AccessAbstract

Synthesis of New N-Substituted N′-(2-methylthio-4-chloro-5-methylbenzenesulfonyl)guanidines with Anticancer Activity

by Beata Żołnowska, Jarosław Sławiński and Anna Kawiak

Med. Sci. Forum 2022, 14(1), 42; https://doi.org/10.3390/ECMC2022-13255 - 1 Nov 2022

Viewed by 659

Abstract

Cancer is a disease that has spread widely throughout the world and requires the development of new anticancer drugs. Curing cancer is a complicated process as the drugs that are used target human cells and cells that have undergone genetic changes and are [...] Read more.

Cancer is a disease that has spread widely throughout the world and requires the development of new anticancer drugs. Curing cancer is a complicated process as the drugs that are used target human cells and cells that have undergone genetic changes and are dividing at a quick and uncontrolled rate. Thus, there is a constant need to develop alternative or synergistic anticancer agents with minimal side effects. One of the important strategies in the search for chemotherapeutics is the approach based on combining fragments of known drugs in one molecule, leading to structures or “hit” structures. The conjugation of two pharmacophores into a molecular hybrid aims at achieving a synergistic effect with increased efficacy compared to the starting compounds. The aim of the work was to synthesize new N-substituted N′-(2-methylthio-4-chloro-5-methylbenzenesulfonyl)guanidines with potential anticancer activity, designed as molecular hybrids containing fragments of chalcone and 4-chloro-5-methyl-2-methylthiobenzenesulfonamide. Cytotoxic activity of the compounds was evaluated in the MTT test against three human tumor cell lines: breast cancer (MCF-7), colon cancer (HCT-116), and cervical cancer (HeLa). It has been shown that all sulfonamides are highly active against breast and colon cancer cell lines (IC₅₀: 2.5–5 μM). Additionally, in tests carried out on the non-cancer human keratinocyte cell line (HaCaT), it was proved that the tested compounds showed higher cytotoxicity against cancer cells compared to healthy cells. Cytotoxic activity in the HeLa cell line ranged from values of IC₅₀ from 5 to 17 μM. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 207 KiB

Open AccessAbstract

Fumiquinazoline-Related Alkaloids with Antibacterial, Anti-Biofilm and Efflux Pump Inhibition Properties

by Mariana C. Almeida, Nikoletta Szemerédi, Fernando Durães, Diana I. S. P. Resende, Paulo Martins da Costa, Madalena Pinto, Gabriella Spengler and Emília Sousa

Med. Sci. Forum 2022, 14(1), 43; https://doi.org/10.3390/ECMC2022-13440 - 1 Nov 2022

Viewed by 718

Abstract

With antimicrobial resistance reaching critical levels worldwide, the development of new compounds that are effective against resistant bacterial pathogens or that can potentiate the effect of known antibiotics is an urgent need. The formation of biofilms and the overexpression of efflux pumps are [...] Read more.

With antimicrobial resistance reaching critical levels worldwide, the development of new compounds that are effective against resistant bacterial pathogens or that can potentiate the effect of known antibiotics is an urgent need. The formation of biofilms and the overexpression of efflux pumps are some of the most common causes of drug resistance. Previous work from our group has shown that alkaloids related to the fumiquinazolines have antibacterial potential. Herein we aimed to synthesize a small library of fumiquinazoline-related alkaloids and to study their antibacterial and anti-biofilm activities as well as their capacity to inhibit bacterial efflux pumps. To achieve these goals, two naturally occurring alkaloids, as well as several new derivatives, were synthesized through a multi-step synthetic pathway. The screening of their antibacterial activities was achieved by determination of the minimum inhibitory concentration of each compound against a panel of clinically relevant bacterial species. Several compounds exhibited promising activities against Gram-positive bacteria. Then, using the ethidium bromide accumulation assay, it was possible to identify some compounds with capacity to inhibit efflux pumps. Some of the synthesized alkaloids also showed anti-biofilm potential, reinforcing the idea that fumiquinazoline-related alkaloids can constitute a key strategy for fighting antimicrobial resistance. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 186 KiB

Open AccessAbstract

Combination Therapy Assays with Doxorubicin and Cathepsin L Inhibitors against the Triple-Negative Breast Cancer Line MDA-MB-231

by Talita Alvarenga Valdes, Isabela Marques and Andrei Leitao

Med. Sci. Forum 2022, 14(1), 44; https://doi.org/10.3390/ECMC2022-13485 - 2 Nov 2022

Viewed by 790

Abstract

Breast cancer is a worldwide health problem as one of the most prevalent types of tumors in the female population. Despite the availability of many therapies, including doxorubicin, novel chemotherapeutic approaches are being studied for this disease, focusing on triple-negative breast cancer cells. [...] Read more.

Breast cancer is a worldwide health problem as one of the most prevalent types of tumors in the female population. Despite the availability of many therapies, including doxorubicin, novel chemotherapeutic approaches are being studied for this disease, focusing on triple-negative breast cancer cells. Cathepsin L is a cysteine protease that is highly expressed in many tumors, where novel dipeptidyl nitrile inhibitors have been designed and studied over time in our research group. Here, an approach involving the combination therapy of twelve novel cathepsin L inhibitors and doxorubicin was assayed against the triple-negative human breast cancer cell line MDA-MB-231. The cells were cultivated using DMEM medium supplemented with 10% FBS. They were added to 96-plates at a concentration of 1.0 × 10⁴ cells/well. After 24 h of incubation, the medium was removed to add 10 micromolar cathepsin L inhibitors and a range of doxorubicin concentrations (1.0-1 nanomolar). The system was incubated for 72 h before being subjected to MTT assays. The Bliss test was used to evaluate the concentration-dependent assay of these chemicals, which led to synergism for many chemicals. The best combination led to almost 8-times higher potency improvement than doxorubicin alone. The SAR was described for this set of dipeptidyl nitriles. It is not yet known how these chemicals could act in combination, and this is the current focus of our efforts to exploit the biological mechanisms. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 215 KiB

Open AccessAbstract

Polyvinylpyrrolidone-Coated Silver Nanoparticles Induce the Expression of Inducible Nitric Oxide Synthase in Intestinal C2BBe1 Cells

by Adelaide Sousa, Ana Ramalho, Félix Carvalho, Eduarda Fernandes and Marisa Freitas

Med. Sci. Forum 2022, 14(1), 45; https://doi.org/10.3390/ECMC2022-13196 - 1 Nov 2022

Viewed by 662

Abstract

Silver nanoparticles (AgNP) have gained access to our daily life, resulting in exponential and inevitable human exposure, namely by the oral route. Despite this, the adverse effects of AgNP on intestinal cells are still unexplored. Thus, this study aimed to investigate the potentially [...] Read more.

Silver nanoparticles (AgNP) have gained access to our daily life, resulting in exponential and inevitable human exposure, namely by the oral route. Despite this, the adverse effects of AgNP on intestinal cells are still unexplored. Thus, this study aimed to investigate the potentially toxic and pro-inflammatory effects of polyvinylpyrrolidone (PVP)-coated AgNP (5 and 50 nm) in intestinal epithelial C2BBe1 cells. For this purpose, the effects of PVP-AgNP on cellular metabolic activity and viability, and also on the expression levels of inducible nitric oxide synthase and iкBα, were evaluated. It was observed a decrease in cellular metabolic activity, associated with the occurrence of early and late apoptotic events, for the 50 nm PVP-AgNPs. The expression levels of inducible nitric oxide synthase and iкBα levels increased and decreased, respectively, after exposure to 50 nm PVP-AgNP. Ultimately, it was also observed an increase in nitric oxide levels. Therefore, it can be concluded that the larger PVP-AgNP induce prominent activation of a putative inflammatory response by intestinal cells. However, further studies are needed to disclose the mechanistic pathways involved in the intestinal pro-inflammatory effects of AgNP. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 187 KiB

Open AccessAbstract

Synthesis and Antifungal Activity of Thioxanthone Derivatives

by Joana Cardoso, Joana Freitas-Silva, Fernando Durães, Madalena Pinto, Emília Sousa and Eugénia Pinto

Med. Sci. Forum 2022, 14(1), 46; https://doi.org/10.3390/ECMC2022-13478 - 1 Nov 2022

Viewed by 737

Abstract

Systemic fungal infections caused by filamentous fungi, particularly in the immunocompromised population, represent a serious threat to public health. The increase in resistant strains to classic antifungal drugs, especially azoles, is a global health problem, with some infections becoming almost impossible to treat. [...] Read more.

Systemic fungal infections caused by filamentous fungi, particularly in the immunocompromised population, represent a serious threat to public health. The increase in resistant strains to classic antifungal drugs, especially azoles, is a global health problem, with some infections becoming almost impossible to treat. Furthermore, the emergence of new multidrug-resistant fungal species, such as Scedosporium spp. and Fusarium spp., as etiological agents, poses a challenge in treatment. On the other hand, superficial fungal infections caused by dermatophytes have a high incidence rate, affecting approximately 20 to 30% of the healthy human population. Therefore, the discovery and development of new broad-spectrum antifungal compounds able to modulate and/or eradicate antifungal resistance have become an essential and urgent task. Taking into account that thioxanthones are privileged structures and bioisosteres of xanthones, three thioxanthones were synthesized and, subsequently, their activity as potential agents against filamentous fungi was evaluated. A minimum inhibitory concentration and minimum lethal concentration was tested against clinically relevant species using the broth microdilution method. The derivatives were synthesized through aromatic nucleophilic substitution reactions using a chlorinated thioxanthone and a primary amine as the building blocks. This showed interesting results against most of the isolates tested, including intrinsically resistant strains or those that acquired resistance to fluconazole or other azoles; among the tested compounds, one of the thioxanthone showed more promising activity. These findings highlight the potential value of thioxanthone derivatives as new models for antifungal agents for the treatment of systemic and superficial fungal infections. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 189 KiB

Open AccessAbstract

Preparation and Evaluation of Cucumber Seed Extract Sunscreen

by Xiyue Wang, Man Teng, Xinhui Pan and Xiaoda Yang

Med. Sci. Forum 2022, 14(1), 47; https://doi.org/10.3390/ECMC2022-13314 - 1 Nov 2022

Cited by 1 | Viewed by 1802

Abstract

Cucumber seeds are the seeds of Cucumber (Cucumis sativus L.), which include a large number of essential fatty acids, plant sterols, glycosides, volatile oils, as well as Ca, Mg, and other inorganic elements. Cucumber seed oil has good UV absorption effect because [...] Read more.

Cucumber seeds are the seeds of Cucumber (Cucumis sativus L.), which include a large number of essential fatty acids, plant sterols, glycosides, volatile oils, as well as Ca, Mg, and other inorganic elements. Cucumber seed oil has good UV absorption effect because it is rich in an unsaturated functional group structure. Plant sterol in cucumber seed oil shows strong permeability toward the skin, which promotes skin metabolism and inhibits skin inflammation. β-sitosterol in plant sterols can also effectively protect the peroxide of low-density lipoprotein, so they have an antioxidant effect. In this study, cucumber seed oil was extracted by the Soxhlet extraction method as plant-based sunscreen, in which cucumber seed oil was used as the main component, and an appropriate amount of titanium dioxide was used as an antioxidant. Taking the settling solvent ratio as the index, the orthogonal experiment was designed to determine the prescription composition of the pure matrix. Then the single factor experiments of cucumber seed oil, titanium dioxide, and vitamin E were carried out. The effects of three components on UV absorption were investigated by orthogonal experiments, and the optimum formula with cucumber seed oil as the main component was finally determined and verified. In conclusion, our plant sunscreen was produced by cucumber seed oil as raw material instead of hormone. There was no harm to the skin. It has the potential to develop plant-based sunscreen with cucumber seed oil and provides a reference for the development of plant sunscreen and skin care products. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Identification of New Anti-SARS CoV-2 Agents through theVirtual Screening of Phytoconstituents Extracted from Moroccan Plants

by Oussama Abchir, Hassan Nour, Ossama Daoui, Souad El Khattabi and Samir Chtita

Med. Sci. Forum 2022, 14(1), 48; https://doi.org/10.3390/ECMC2022-13480 - 1 Nov 2022

Viewed by 773

Abstract

The rapid spread of fatal diseases forces us to reconsider our position as researchers in the field of drug development assisted by computers. On the other hand, new drugs are constantly being developed from natural compounds using computer-aided methods. Virtual screening is carried [...] Read more.

The rapid spread of fatal diseases forces us to reconsider our position as researchers in the field of drug development assisted by computers. On the other hand, new drugs are constantly being developed from natural compounds using computer-aided methods. Virtual screening is carried out in accordance with the protocols established by accredited organizations and is based on the structure of the ligands or the structure of the target proteins. The formation of a database based on phytotherapy is the best option because Morocco is known for its wealth of plants and their traditional uses in medicine, which encourages us to better utilize our cultural heritage and the natural diversity of our country in the therapeutic field. The combination of these fields of CADD and phytotherapy can yield positive results in terms of the development of molecules with the goal of their use as drugs that are capable of inhibiting a pathological protein. In the present study, deep research was performed to collect a set of phytoconstituents extracted from Moroccan plants in order to evaluate their ability to limit the proliferation of SARS-CoV-2. Molecular docking was performed in the active sites of the 6lu7 and 6m0j proteins to assess their binding affinity. The structural stability of the target proteins was validated by redocking. The compounds with good binding affinity values were further subjected to Lipinski’s rule of five, chemical absorption and toxicity analysis. The results revealed that only two of the compounds presented a good binding affinity towards the target proteins and are able to be used as orally available medication for SARS-CoV-2. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 180 KiB

Open AccessAbstract

New N-Benzenesulfonylguanidine Derivatives and Their Selective Growth Inhibition of Human Breast Cancer Cell Line MCF-7 and Colon Carcinoma HCT-116

by Aneta Pogorzelska, Jarosław Sławiński and Anna Kawiak

Med. Sci. Forum 2022, 14(1), 49; https://doi.org/10.3390/ECMC2022-13281 - 1 Nov 2022

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Abstract

Our previous research proved that benzenesulfonylguanidine derivatives display significant cytotoxic activity against human cancer cells. Here, we describe new 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines with cytotoxic activity against HCT-116 and MCF-7 cells. The planned derivatives were obtained by a two-step synthesis. The starting substrates were 1-(2-alkylthio-4-chloro-5-methyl)benzenesulfonyl)-3-aminoguanidines 1 [...] Read more.

Our previous research proved that benzenesulfonylguanidine derivatives display significant cytotoxic activity against human cancer cells. Here, we describe new 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines with cytotoxic activity against HCT-116 and MCF-7 cells. The planned derivatives were obtained by a two-step synthesis. The starting substrates were 1-(2-alkylthio-4-chloro-5-methyl)benzenesulfonyl)-3-aminoguanidines 1–4, which were transformed into 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-3-[(2-chloroacetyl)amino]guanidines 5–8 by a reaction with chloroacetyl chloride. In the next step, the derivatives 5–8 were reacted with potassium thiocyanate, yielding 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-3-(2-imino-4-oxothiazolidine-3-yl)guanidines 9–12. The synthesized derivatives 5–12 were evaluated in vitro by MTT assays for their activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7, and cervical cancer HeLa. The activity against non-cancerous human epidermal keratinocyte line HaCaT was also examined. The data indicate that compounds 5–8 inhibit the growth of cancer cells more strongly than derivatives 9–12. The selective cytotoxic effect against HCT-116 cells was found for benzenesulfonylguanidine 6 containing a 2-(trifluoromethyl)benzylthio group at position two of the benzenesulfonyl scaffold. The IC₅₀ value was 13 μM, while IC₅₀ for HaCaT cells, it was 48 μM. Good selectivity was also observed for compound 7, with a 2-chloromethylbenzylthio substituent, against HCT-116 and MCF-7 cells (IC₅₀ = 12 and 19 μM, respectively, for HCT-116 and MCF-7 cells, IC₅₀ = 47 μM for HaCaT cells). Among compounds 9–12, only compound 9 showed moderate but selective cytotoxicity against MCF-7 cells, with IC₅₀ = 18 μM compared with IC₅₀ = 54 μM for HaCaT cells. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 211 KiB

Open AccessAbstract

Natural Brewing Peptides with Enhanced Inhibitory Effects on Angiotensin I-Converting Enzyme

by Rita Ribeiro-Oliveira, Zita E. Martins, Miguel Ângelo Faria, Joana Beatriz Sousa, Isabel M. P. L. V. O. Ferreira and Carmen Diniz

Med. Sci. Forum 2022, 14(1), 50; https://doi.org/10.3390/ECMC2022-13426 - 1 Nov 2022

Cited by 1 | Viewed by 840

Abstract

Angiotensin-converting enzyme (ACE) inhibitors are anti-hypertensive drugs associated with several side effects. Natural compounds, namely bioactive peptides from brewing by-products—brewer’s spent grain (BSG) and yeast (BSY)—are promising alternatives, as they can inhibit ACE in vitro and are less likely to cause severe side [...] Read more.

Angiotensin-converting enzyme (ACE) inhibitors are anti-hypertensive drugs associated with several side effects. Natural compounds, namely bioactive peptides from brewing by-products—brewer’s spent grain (BSG) and yeast (BSY)—are promising alternatives, as they can inhibit ACE in vitro and are less likely to cause severe side effects, while maintaining therapeutic efficacy. However, the impact of oral administration on peptides’ bioavailability has not been assessed so far. Thus, the aim of this study was to understand in vitro the impact of the oral route on the effectiveness of BSG/BSY peptides as ACE inhibitors. Extracted BSG/BSY proteins were hydrolysed and sequentially subjected to simulated gastrointestinal digestion (INFOGEST), intestinal absorption and liver metabolism (co-culture of Caco-2 and HepG2 cells). MTT assay was used to assess BSG/BSY peptides’ safeness. The ACE-inhibitory potential of initial and final products (BSY, BSG and a mixture 50:50—MIX) at an identical concentration (0.857mg/mL) was measured (fluorometric assay) and compared with Captopril (1 µM, a clinically used ACE-inhibitory drug). Simulation of oral administration increased brewing peptides’ ACE-inhibitory capacity. When comparing the final peptides with captopril, BSY demonstrated identical potency, while BSG showed 22% greater efficacy; the new tested product MIX presented 30% higher inhibition. In conclusion, the current study shows that BSG, BSY and MIX natural peptides derived from the brewing industry enhance their bioactive properties as ACE-inhibitors after oral administration, validating the usefulness of these peptides to reduce the risk of, ameliorate or treat primary hypertension. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 179 KiB

Open AccessAbstract

Anticancer Evaluation of 4-substituted-N-(quinolin-8-yl)pyridine-3-sulfonamides

by Krzysztof Szafrański, Jarosław Sławiński and Anna Kawiak

Med. Sci. Forum 2022, 14(1), 51; https://doi.org/10.3390/ECMC2022-13280 - 1 Nov 2022

Cited by 1 | Viewed by 664

Abstract

During our research of biological activity of different N-aryl-4-substututed-pyridine-3-sulfonamides, we have found that compounds bearing a N-(quinolin-8-yl) substituent possess a significant anti-tumor activity. Mechanisms of anticancer activity of N-(quinoline)sulfonamide derivatives were reported to be inhibitors of the NF-κB pathway. Nuclear [...] Read more.

During our research of biological activity of different N-aryl-4-substututed-pyridine-3-sulfonamides, we have found that compounds bearing a N-(quinolin-8-yl) substituent possess a significant anti-tumor activity. Mechanisms of anticancer activity of N-(quinoline)sulfonamide derivatives were reported to be inhibitors of the NF-κB pathway. Nuclear factor NF-κB regulates expression of genes that control cell proliferation and cell survival; thus, it is considered a potential molecular target for the prevention and treatment of cancer. Based on this information, we decided to synthesize and evaluate a series of 4-amino-N-(quinolin-8-yl)pyridine-3-sulfonamides, which contain both a 8-amonoquinolin group and a pyridine-3-sulfonamide scaffold. Target compounds were obtained in a multistep reaction starting from 4-hydroxypyridine, and their structure was confirmed using the spectroscopic methods: IR, ¹H NMR, and elemental analysis (C, H, N). Synthesized compounds were tested using a tetrazolium (MTT) cell viability assay towards their effect on growth of three human cancer cell lines (colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa) and on the noncancerous keratinocyte cell line HaCaT. Cell viability was measured after 72 h of incubation with the tested compound in five concentrations (1–100 μM). All compounds show very high activity compared to cisplatin against cancer cells lines (IC₅₀ = 4–43 μM), and a selectivity relative to HaCaT cells. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 207 KiB

Open AccessAbstract

Synthesis, Docking Studies and Acetylcholinesterase Inhibition of Open-Chain Carbohydrate Amides

by Maria Isabel Ismael, Rita Gonçalves-Pereira, Susana D. Lucas, José Albertino Figueiredo, Maria Isabel García-Moreno, Carmen Mellet and Amélia Pilar Rauter

Med. Sci. Forum 2022, 14(1), 52; https://doi.org/10.3390/ECMC2022-13483 - 1 Nov 2022

Viewed by 694

Abstract

Alzheimer’s disease (AD) is the most common age-related cause of dementia among elderly people. AD is a severe neurodegenerative disorder characterized by progressive memory and cognition loss that leads to disability and inevitably to death and is considered as an urgent public health [...] Read more.

Alzheimer’s disease (AD) is the most common age-related cause of dementia among elderly people. AD is a severe neurodegenerative disorder characterized by progressive memory and cognition loss that leads to disability and inevitably to death and is considered as an urgent public health problem. It is the third leading cause of death after cancer and heart disease. According to an update in 2020 of the estimates given in the World Alzheimer Report 2015, there are over 50 million people worldwide living with dementia in 2020. This number will almost double every 20 years, reaching 152 million in 2050. AChE inhibitors are the mainstay drugs for early disease stages. In this work we report on the development of a synthetic route to yield open chain sugar amides from commercially available carbohydrates. The synthetic pathway starts with diacetone glucose (DAG), which is converted into perbenzyl d-glucono-1,4-lactone in six steps. Reaction with aromatic or aliphatic amines in dichloromethane under reflux (0.5 h to 2 h) afforded the corresponding amides in high yield (80–95%). Bis(amidation) of a diamine was also accessed by this procedure in 3 h but the reaction product was isolated in a very low yield (13%). Docking studies and evaluation of acetylcholinesterase inhibition were carried out and the results will be disclosed. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 209 KiB

Open AccessAbstract

Steroids Conjugated to Carbon Nanoforms as Potential Inhibitors of Viral Proteases, Synthesis, DFT Calculations, and Molecular Docking

by Reinier Lemos, Kamil Makowski and Margarita Suárez

Med. Sci. Forum 2022, 14(1), 53; https://doi.org/10.3390/ECMC2022-13243 - 1 Nov 2022

Viewed by 663

Abstract

Steroid [60]fullerene hybrids have been synthesized by the Bingel−Hirsch reaction as a contribution to the chemistry of carbon nanoforms. The hybrids were characterized by different spectroscopic experiments and analytical techniques. Theoretical calculations using the Density functional theory and the PBE functional were performed [...] Read more.

Steroid [60]fullerene hybrids have been synthesized by the Bingel−Hirsch reaction as a contribution to the chemistry of carbon nanoforms. The hybrids were characterized by different spectroscopic experiments and analytical techniques. Theoretical calculations using the Density functional theory and the PBE functional were performed to predict the most stable conformations for the synthesized compounds and the frontier molecular orbitals energy. Some properties, such as polarizability, dipole moment, lipophilicity, solvent-accessible surface area, and topological polar surface area, were calculated. Fullerenes and their derivatives have potential antiviral activity due to their specific binding interactions with biological molecules. The ability of fullerene derivatives to interact with the active site of HIV and SARS-Cov-2 proteases was studied by the Autodock Vina program. The C₆₀ cage exhibited an interaction with the phenyl group of phenylalanine residues through π–π and T-shape interactions. Furthermore, it was observed that the steroid moieties formed H-bonds with the amino acid residues in the active sites of proteins. In addition, van der Waals contacts with the nonpolar protease surface, thereby improving the binding relative to the tested compound. Protein-ligand docking revealed several important molecular fragments that are responsible for the interaction, thus paving the way to study the possible application of these hybrids in medicinal chemistry. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 202 KiB

Open AccessAbstract

Comparative Clinical Efficacy Study between Erenumab and Fremanezumab

by Raquel Fresquet, Lucia Sopena, Jose Manuel Vinuesa, Aritz Merchan, Lucía Cazorla, Maria Perez, Alberto Frutos, Mercedes Arenere, Maria del Puerto Pardo, Maria de los Ángeles Allende and Tránsito Salvador

Med. Sci. Forum 2022, 14(1), 54; https://doi.org/10.3390/ECMC2022-13227 - 1 Nov 2022

Viewed by 932

Abstract

A retrospective comparative study was conducted to compare the efficacy of monoclonal antibody drugs against the calcitonin gene-related peptide pathway in migraine and to establish whether they can be considered equivalent therapeutic alternatives for this pathology. A total of 21 patients with chronic [...] Read more.

A retrospective comparative study was conducted to compare the efficacy of monoclonal antibody drugs against the calcitonin gene-related peptide pathway in migraine and to establish whether they can be considered equivalent therapeutic alternatives for this pathology. A total of 21 patients with chronic migraine were treated with Fremanezumab 225 mg/30 days and 24 patients treated with Erenumab 70 mg/30 days for at least 6 months. Data were collected at baseline and at six months using the following scales: Headache Impact Test (HIT), Migraine Disability Assessment Scale (MIDAS), and a numerical scale of pain intensity (0 (no pain) and 10 (unbearable pain)). Days of migraine per month were recorded. Mean HIT at baseline and 6 months for Fremanezumab and Erenumab was 68.6 (62–76) and 54 (36–70) and 66 (42–78) and 53 (9–72), respectively. In both cases, it decreased by more than 6 points (efficacy criteria). Mean MIDAS at baseline and 6 months for Fremanezumab and Erenumab was 70 (25–127) and 25 (0–135) and 73.3 (19–150) and 23 (0–68), respectively. In both cases, it decreased by more than 30% (efficacy criteria). Mean pain intensity at baseline and 6 months for Fremanezumab and Erenumab was 8.8 (6–10) and 6(5–8) and 8.6 (7–10) and 6 (10–0), respectively. Mean number of migraine days in a month at baseline and 6 months for Fremanezumab and Erenumab were 16.6 (10–30) and 5.3 (0–11) days and 17 (3–30) and 5.8(–15) days, respectively. In both cases, the reduction was > 50%. It can be concluded that the initial values of the scales are very similar. The initial situation of the patient is not a trigger for the use of one drug or the other. Clinically, there is no difference between the two drugs. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 192 KiB

Open AccessAbstract

Evaluation of the Antimicrobial Activity of N-Acylated 4-Chloro-2-mercaptobenzenesulfonamide Derivatives

by Anita Bułakowska, Jarosław Sławiński and Rafał Hałasa

Med. Sci. Forum 2022, 14(1), 55; https://doi.org/10.3390/ECMC2022-13289 - 1 Nov 2022

Viewed by 548

Abstract

Aryl/heteroarylsulfonamides are an important group of compounds with different directions of biological activity. The number of literature reports on the antibacterial activity of sulfonamides is steadily increasing, bringing a lot of interesting data on the diverse structures and mechanisms of their pharmacological action. [...] Read more.

Aryl/heteroarylsulfonamides are an important group of compounds with different directions of biological activity. The number of literature reports on the antibacterial activity of sulfonamides is steadily increasing, bringing a lot of interesting data on the diverse structures and mechanisms of their pharmacological action. The presented research joins the stream of the search for new hybrid molecules being created as a result of the combination of various pharmacophores with interesting biological profiles. Particular attention was paid to their antibacterial activity. The new compounds were designed and obtained based on the structure of the pharmacophore group of 4-chlorobenzenesulfonamide functionalized in the 2-position on sulfur atom, and the structure of chalcone. Taking into account the previous results of our own research and the available literature data, new N-(4-chloro-2-arylmethylthio-5-methylphenylsulfonyl)cinnamamide derivatives were designed and synthesized, which have pharmacophore groups in their structure, such as: 1-naphthylmethylthio and 6-chloropiperonylthio. Preliminary microbiological analysis was performed using TLC-bioautography. The expected antibacterial activity of the obtained compounds was confirmed inin vitrotests against Gram-positive bacteria: S. aureus, S. epimermidis, E. hirae, E. faecalis, and B. subtilis. In the next stage, the microbiological activity of selected compounds against clinical strains MRSA, CNS, and MRSE was also tested. The derivatives’ activity against bacterial biofilm and hemolytic activity on the peripheral blood of domestic sheep were also tested. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 180 KiB

Open AccessAbstract

Larger Particle Size Results in Longer Lung Retention Time of Inhaled Solid Lipid Nanoparticles

by Zhengwei Huang, Jiajun Chen, Chuanbin Wu and Xin Pan

Med. Sci. Forum 2022, 14(1), 56; https://doi.org/10.3390/ECMC2022-12913 - 26 Sep 2022

Viewed by 740

Abstract

Aims: The particle size–lung retention time correlation is a vital guiding principle in developing pulmonary nanoparticle drug delivery systems (PNDDS). Fluorescence probes with accurate water-quenching attributes, which are emissive under PNDDS encapsulation while quenched upon release into physiological environments, reflect the fluorescence signals [...] Read more.

Aims: The particle size–lung retention time correlation is a vital guiding principle in developing pulmonary nanoparticle drug delivery systems (PNDDS). Fluorescence probes with accurate water-quenching attributes, which are emissive under PNDDS encapsulation while quenched upon release into physiological environments, reflect the fluorescence signals of intact PNDDS, and thus, unambiguously clarify the lung retention profile of PNDDS. Herein, the water-quenching probe P2 was used to investigate the particle size–lung retention time correlation. Methods: P2 was donated by Prof. Wei Wu (Fudan University, Shanghai, China). P2-loaded PNDDS, viz. solid lipid nanoparticles (SLN) of different sizes, were prepared via high-pressure homogenization, and encoded as P2-SLN1~P2-SLN4. The particle sizes of P2-SLN1~P2-SLN4 were measured, and then, endotracheally aerosolized in male BALB/c mice (22~26 g), and the P2 fluorescence signals were detected via live imaging. Half-life (T_1/2) and mean retention time (MRT_0–∞) were computed using WinNonlin to describe lung retention time. T_1/2 or MRT_0–∞ was plotted against particle size, and linear regression was performed. Results: P2-SLN1~P2-SLN4 possessed average sizes of circa 120, 240, 360 and 480 nm, respectively, with good size-distribution homogeneity. After inhalation, P2 fluorescence intensity continuously decreased in the pulmonary region. Noticeably, T_1/2 and MRT_0–∞ were positively correlated with particle size, with great model fitness (R² > 0.99, p > 0.05). Therefore, larger particle size (within the range of 120~480 nm) caused longer retention time. Conclusions: A positive particle size–lung retention time correlation in SLN was demonstrated. For the development of PNDDS, appropriately increasing the particle size enhances lung retention, and vice versa. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 175 KiB

Open AccessAbstract

Selective Biomarkers of Oxidative Stress in Ischemic Stroke

by Hanna Pawluk, Renata Kołodziejska, Grzegorz Grześk, Mariusz Kozakiewicz, Grzegorz Kozera, Mateusz Pawluk, Agnieszka Kosinska, Magdalena Grześk, Elżbieta Grzechowiak and Alina Woźniak

Med. Sci. Forum 2022, 14(1), 57; https://doi.org/10.3390/ECMC2022-13156 - 1 Nov 2022

Viewed by 705

Abstract

Stroke is a serious health problem all over the world and the second most common cause of death and permanent disability in people, after heart attacks. Oxidative stress plays an important role in the pathogenesis of acute ischemic stroke (AIS). The aim of [...] Read more.

Stroke is a serious health problem all over the world and the second most common cause of death and permanent disability in people, after heart attacks. Oxidative stress plays an important role in the pathogenesis of acute ischemic stroke (AIS). The aim of our study was to evaluate the temporal profile of the melatonin metabolite 6-hydroxymelatonin sulphate (6-SM) in the urine and carbonyl groups in the serum of patients with acute ischemic stroke treated with intravenous thrombolysis. There were statistically significant differences between the values of 6-SM and carbonyls compared to the control group. Statistical differences were also found in the concentrations of the examined parameters depending on the type of stroke. The correlations between the concentrations of 6-SM and the carbonyl groups measured in various time intervals and between the concentration of biomarkers and mortality was also evaluated. The results indicate increased oxidative stress and the intense increase in the concentration of carbonyl groups in patients with AIS, which could be potential markers of protein damage in thrombolytic patients. Melatonin supplementation in AIS patients can also be considered, as it can effectively prevent both behavioral and neurophysiological defects caused by cerebral hypoxia and ischemia. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 185 KiB

Open AccessAbstract

Synthesis, Structure and Biological Activity of Novel 4,5-dihydro-1H-imidazol-2-yl-phthalazine Derivatives and Their Copper(II) Complexes

by Łukasz Balewski, Jakub Kokoszka, Joanna Fedorowicz, Polina Ilina, Päivi Tammela, Maria Gdaniec and Anita Kornicka

Med. Sci. Forum 2022, 14(1), 58; https://doi.org/10.3390/ECMC2022-13272 - 1 Nov 2022

Viewed by 731

Abstract

As a continuation of our previous investigations aimed at the synthesis of novel nitrogen-containing heterocycles and their metal complexes, we have now prepared two series of compounds incorporating a phthalazine ring at the position C₂ of 4,5-dihydro-1H-imidazole. The starting phthalazine [...] Read more.

As a continuation of our previous investigations aimed at the synthesis of novel nitrogen-containing heterocycles and their metal complexes, we have now prepared two series of compounds incorporating a phthalazine ring at the position C₂ of 4,5-dihydro-1H-imidazole. The starting phthalazine (I) in the reaction with 2-chloroimidazoline (II) gives rise to the formation of pseudobase III. Then, compound III upon treatment with HOSA yields betaine which under basic conditions gives 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (IV). In turn, the reactions of compound IV with a variety of acyl and sulfonyl chlorides lead to the formation of benzamides (V) and benzenesulfonamides (VI). Moreover, compounds V and VI can be transformed into corresponding 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one derivatives VII and VIII. Such ligands are susceptible to the reaction with CuCl₂ giving rise to the formation of corresponding copper(II) complexes: dichloro[2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine]copper(II) (1), dichloro[2-(1-benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]copper(II) (2) and dichloro{bis-[2-(1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]}copper(II) (3). The most promising results of biological studies were obtained for complex 1 towards the HeLa cell line (IC₅₀ = 2.13 μM) without a toxic effect against fibroblasts BALB/3T3 (IC₅₀ = 135.30 μM), which pointed towards its selectivity as a potential antitumor agent. It should be pointed out, that corresponding free ligand 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (IV) was less active than its metal complex (IC₅₀ = 87.74 μM). Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 222 KiB

Open AccessAbstract

In Vitro Cytotoxicity of 7,3′,4′-Trihydroxyflavones in Lung Fibroblasts

by Isabela Santos, Hélio M. T. Albuquerque, Artur M. S. Silva, Eduarda Fernandes and José Miguel P. Ferreira de Oliveira

Med. Sci. Forum 2022, 14(1), 59; https://doi.org/10.3390/ECMC2022-13254 - 1 Nov 2022

Viewed by 753

Abstract

According to the World Health Organization (WHO), cancer is the second cause of death globally. Conventional cancer therapy includes surgery, chemotherapy, and radiotherapy. Nevertheless, therapy is often limited by low efficacy or significant adverse side effects. Therefore, safer and more efficient therapeutic agents [...] Read more.

According to the World Health Organization (WHO), cancer is the second cause of death globally. Conventional cancer therapy includes surgery, chemotherapy, and radiotherapy. Nevertheless, therapy is often limited by low efficacy or significant adverse side effects. Therefore, safer and more efficient therapeutic agents are essential. Flavonoids, compounds largely found in the plant kingdom, have shown promising cancer-inhibiting properties. Although the cytotoxic effect of flavonoids in human cancer cell lines is widely reported, the corresponding effect in healthy human cells is underreported. The present study aims to evaluate the toxicity of a group of flavonoids hydroxylated at C-7, C-3′, and C-4′ in lung fibroblasts. To achieve this, the MRC-5 human lung fibroblast cell line was incubated with flavonoids, 0–160 µM, with additional hydroxy groups at C-3, C-6, or C-5′, or chlorine at C-3. After incubation for 48 h, the inhibition of cell viability and growth was measured using WST-8 and sulforhodamine B assays, respectively. The presence of the 3- or 5-hydroxy groups was associated with lower cytotoxicity at low concentrations (40 µM); meanwhile, at higher concentrations (>40 µM), only the presence of the 5-hydroxy group seemed to be related to low cytotoxicity. Although additional studies are required, these results reveal substituted flavonoids with lower in vitro toxicity in healthy human cells. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 170 KiB

Open AccessAbstract

Synthesis, In Silico and In Vitro Studies of 7-Methxy-3-((4-phenyl piperazin-1-yl)methyl)-2H-chromen-2-one Analogues as Derivatives as Anti-Prostate Cancer Agents

by Arjun H. Ananth and Senthamaraikannan Kabilan

Med. Sci. Forum 2022, 14(1), 60; https://doi.org/10.3390/ECMC2022-13179 - 1 Nov 2022

Viewed by 756

Abstract

One of the most common diseases found among men in recent days is prostate cancer (PCa). The growth of cancer is generally due to the activation of the androgen receptor by androgens. Structural modification and molecular docking approaches were done with the protein [...] Read more.

One of the most common diseases found among men in recent days is prostate cancer (PCa). The growth of cancer is generally due to the activation of the androgen receptor by androgens. Structural modification and molecular docking approaches were done with the protein (PDB ID: 3A49) to identify the novel 7-methxy-3-((4-phenylpiperazin-1-yl)methyl)-2H-chromen-2-one derivatives. The compounds (5a-g) was synthesized and characterized well by IR, NMR, and LC-MS spectral techniques. The compound 5a and 5b were reconfirmed by single crystal XRD. The in vitro anticancer studies were carried out for the compounds (5a-g) against LNCaP, Pc3 and 3T3 cell line. Among them 5b showed highest cytotoxicity against LNCAP (10.45 ± 1.32) μM, Pc3 (34.65 ± 1.36) μM and reduced cell viability. For the compound 5b, simulations of molecular dynamics are conducted to test protein-ligand interactions. Drug similarity and pharma kinetic properties for all compounds were anticipated. The outcome of these results may give vital information in further development. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 200 KiB

Open AccessAbstract

Resveratrol-Loaded Glycosylated Liposomes for Targeting Bacteria

by Cecilia Bombelli, Livia Pagano, Stefano Aiello, Foteini Gkartziou, Beatrice Simonis, Francesca Ceccacci, Simona Sennato, Alessia Ciogli, Francesca Bugli, Cecilia Martini, Maurizio Sanguinetti, Riccardo Torelli, Spyridon Mourtas, Iris Spiliopoulou, Sophia G. Antimisiaris and Giovanna Mancini

Med. Sci. Forum 2022, 14(1), 61; https://doi.org/10.3390/ECMC2022-13158 - 1 Nov 2022

Cited by 2 | Viewed by 1112

Abstract

Biofilm-associated bacterial diseases are a major health problem due to the high antibiotic resistance of biofilm infections [...] Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 202 KiB

Open AccessAbstract

The Journey towards Solubility Assessment of Small Molecules Using HPLC-DAD

by Nada Hemmani, Anaïs Cacilie Martin, Andy Larivière, Mathis Tresallet, Kensa Tchang, Isabelle Krimm and Marc Le Borgne

Med. Sci. Forum 2022, 14(1), 62; https://doi.org/10.3390/ECMC2022-13143 - 1 Nov 2022

Viewed by 788

Abstract

In the process of developing bioactive small molecules, solubility determination is a crucial step. Many research papers treating problems related to solubility are published, but none of them fully describes the methods and steps for solubility assessment. In addition, in silico prediction tools [...] Read more.

In the process of developing bioactive small molecules, solubility determination is a crucial step. Many research papers treating problems related to solubility are published, but none of them fully describes the methods and steps for solubility assessment. In addition, in silico prediction tools and databases such as SwissADME, ACD/Percepta, DrugBank and many others offer the possibility to have approximative solubility values based on the structure of the molecule. Although significant differences can be observed depending on the database and the conditions of the experiment such as solvent, pH, temperature… etc. The lack of data can be a barrier to obtaining details on solubility measurement methods. This presentation aims to describe, step by step, the journey of tryptophan solubility determination using high-performance liquid chromatography-diode array detector (HPLC-DAD). Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 162 KiB

Open AccessAbstract

Rapid and Synchronized Dormancy-Breaking Jumbo Leek Bulb Inhibits Postprandial Carbohydrate Degradation and Absorption to Be Assumed Preprandial Ingestion

by Toshihiro Ona and Junko Johzuka

Med. Sci. Forum 2022, 14(1), 63; https://doi.org/10.3390/ECMC2022-13270 - 1 Nov 2022

Viewed by 620

Abstract

In order to prevent obesity and diabetes, it is important to avoid overeating, especially carbohydrates. Therefore, we evaluated the effect of taking a jumbo leek bulb before a meal on the decomposition and absorption inhibition of carbohydrates after a meal. In this case, [...] Read more.

In order to prevent obesity and diabetes, it is important to avoid overeating, especially carbohydrates. Therefore, we evaluated the effect of taking a jumbo leek bulb before a meal on the decomposition and absorption inhibition of carbohydrates after a meal. In this case, we used a product that had been heat-treated after rapid and synchronized dormancy-breaking (RSDB) had been used to promote phase transition of its content, and we investigated by decreasing two enzyme activities, namely pancreatic α-amylase and α-glucosidase, and reported the results. In the case of pancreatic α-amylase, the untreated (heated and lyophilized) without RSDB showed a 6.5% inhibition of enzyme activity when compared to the control. In contrast, the RSDB inhibited it more effectively by 12.5%. In the case of α-glucosidase, the untreated group had 9.1% inhibition of enzyme activity, whereas the RSDB treatment had 14.6% inhibition, which was about 1.6 times more effective than the untreated group. Thus, the RSDB jumbo leek bulb, when taken before a meal, was found to inhibit postprandial carbohydrate decomposition and absorption (postprandial hyperglycemia prevention effect). It is possible that the inulin in the jumbo leek has an inhibitory effect on glucose absorption by wrapping the carbohydrates, but the RSDB treatment may have accelerated the effect. Furthermore, organosulfur compounds are expected to enhance insulin production and efficiency. In conclusion, the high efficacy of the RSDB jumbo leek in suppressing postprandial carbohydrate degradation and absorption was observed in a model experiment. The RSDB jumbo leek bulb is expected to be effective in preventing obesity and diabetes. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 180 KiB

Open AccessAbstract

Modeling of New VHR Inhibitors Based on 4H-1,3,5-Oxadiazine Derivatives

by Elizaveta R. Lominoga, Pavlo V. Zadorozhnii, Olha O. Hrek, Vadym V. Kiselev and Aleksandr V. Kharchenko

Med. Sci. Forum 2022, 14(1), 64; https://doi.org/10.3390/ECMC2022-13144 - 1 Nov 2022

Viewed by 609

Abstract

Vaccinia H1-related phosphatase (VHR) is a dual-specific phosphatase that is a promising potential target for the treatment of many human diseases. In this work, we have proposed a series of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines as potential VHR inhibitors. The SuperPred online server [...] Read more.

Vaccinia H1-related phosphatase (VHR) is a dual-specific phosphatase that is a promising potential target for the treatment of many human diseases. In this work, we have proposed a series of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines as potential VHR inhibitors. The SuperPred online server predicts VHR inhibition for the studied compounds with a probability of 88.88–98.51%. To establish the efficiency of binding of 4H-1,3,5-oxadiazine derivatives to the active site of VHR (PDB ID: 3F81) in the AutoDock Vina program, we have carried out molecular docking studies. According to the results, the studied compounds effectively interact with the hydrophobic region of the VHR active site due to aromatic rings and the trichloromethyl group, but the polar catalytic cavity is not involved, and therefore inhibition cannot be effective. In this regard, we have built a number of model compounds containing a sulfate group and its derivatives (methyl ester and amide) in the para-position of the arylamine fragment. According to the results of molecular docking, these compounds effectively bind to the polar catalytic cavity of the enzyme due to hydrogen bonds, but due to the relative rigidity of their molecules, hydrophobic interactions are not fully realized. Therefore, in these model compounds between the arylamine fragment and the sulfo group, we introduced a spacer with a length of one to three methylene groups. Hit compounds have been selected—2-(4-((6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-yl)amino)phenyl)ethane-1-sulfonic acid and its amide. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 168 KiB

Open AccessAbstract

Molecular Docking, PASS Prediction, Pharmacokinetic and Toxicity Studies of Focal Adhesion Kinase Inhibitors

by Sahaya Nadar and Tabassum Khan

Med. Sci. Forum 2022, 14(1), 65; https://doi.org/10.3390/ECMC2022-13474 - 1 Nov 2022

Viewed by 948

Abstract

Drug discovery relies on computational medicinal chemistry for designing and identifying new drug-like chemicals, predicting properties and pharmacological activities of molecules, and optimizing lead structures. Focal Adhesion Kinase (FAK) is an emerging target for cancer chemotherapy with mounting evidence that FAK activation or [...] Read more.

Drug discovery relies on computational medicinal chemistry for designing and identifying new drug-like chemicals, predicting properties and pharmacological activities of molecules, and optimizing lead structures. Focal Adhesion Kinase (FAK) is an emerging target for cancer chemotherapy with mounting evidence that FAK activation or elevated expression is associated with cancer progression, invasion, and drug resistance. This work envisages identification and in silico screening of potential FAK inhibitors which could further be evaluated. A total of 862 compounds were screened from the ZINC database and docked on the refined FAK enzyme using Autodock Vina. The best spotted hits were filtered for their drug-likeness using SwissADME. These potential hits were further evaluated for their in silico toxicity using ProTox II software. Promiscuous hits identified by the docking score and applying Lipinski's Rule of Five were ZINC43200601, ZINC95593660, and ZINC95595125. These hits showed high binding scores and passed the colander of in silico pharmacokinetic and toxicity proving these ligands propitious and worthy of further evaluation. For selecting the Activity Spectra for Substances, the PASS program was used to screen the anticancer potential of the compound. The hits displayed an antitumor profile. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 198 KiB

Open AccessAbstract

Glucose Lowering Effects and In Vitro α-Amylase and α-Glucosidase Inhibitory Potential from Aqueous Extract of Adansonia digitata (Baobab) Seed

by Khalifa Umar Bashir and Habibu Tijjani

Med. Sci. Forum 2022, 14(1), 66; https://doi.org/10.3390/ECMC2022-13239 - 1 Nov 2022

Viewed by 740

Abstract

Adansonia digitata L. (Malvaceae, Baobab) is a medicinal tree with antimicrobial, antiviral, anti-inflammatory, and antioxidant properties. The leaves, fruit pulp, stem bark, and roots have been extensively studied. The aim of this study was to evaluate the glucose-lowering and in vitro [...] Read more.

Adansonia digitata L. (Malvaceae, Baobab) is a medicinal tree with antimicrobial, antiviral, anti-inflammatory, and antioxidant properties. The leaves, fruit pulp, stem bark, and roots have been extensively studied. The aim of this study was to evaluate the glucose-lowering and in vitro antidiabetic potentials of the aqueous extract of A. digitata seed. The aqueous extract of A. digitata seed was prepared by dissolving 50 g of powder seed in 500 mL of distilled water for 24 h, filtered using Whatman filter paper, and concentrated using a rotary evaporator at 40 °C. Following an oral administration of glucose (2 g/kg body weight), distilled water, metformin (14.2 mg/kg body weight), and A. digitata seed extracts at 500 and 1000 mg/kg body weight, respectively. The results show that the untreated mice had an average 11.09% increase in plasma glucose concentration, while metformin, aqueous seed extract of A. digitata had average decreases of 17.05%, 0.99%, and 19.21% in plasma glucose concentration, respectively. The aqueous seed extract of A. digitata inhibited α amylase in a concentration-dependent manner with an IC50 of 24.27 ± 2.14 mg/mL compared with acarbose with IC₅₀ of 22.61 ± 1.05 mg/mL. However, the α-glucosidase inhibitory activities of the extract (IC₅₀ 34.37 ± 1.67 mg/mL) were significantly lower compared to acarbose (IC₅₀ 53.46 ± 2.06). The study concludes that aqueous seed extract of A. digitata possesses glucose-lowering properties, in vitro α-amylase and α-glucosidase inhibitory potentials. Further studies will required a bioguided fractionation of aqueous seed extract of A. digitata, to identify its phytochemical constituents using fingerprint chromatography among other techniques. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 182 KiB

Open AccessAbstract

Chromatographic Retention Factor Obtained on Immobilized Keratin Stationary Phase—What Molecular Properties Does It Encode?

by Anna Weronika Sobanska and Elżbieta Brzezińska

Med. Sci. Forum 2022, 14(1), 67; https://doi.org/10.3390/ECMC2022-13242 - 1 Nov 2022

Viewed by 598

Abstract

Chromatographic retention factors (log k_KERATIN) of 33 molecules were obtained on an immobilized keratin stationary phase by Turowski and Kaliszan (J. Pharm. Biomed. Anal. 15, 1997, 1325–1333). Their objective was to develop a novel stationary phase that could be used to [...] Read more.

Chromatographic retention factors (log k_KERATIN) of 33 molecules were obtained on an immobilized keratin stationary phase by Turowski and Kaliszan (J. Pharm. Biomed. Anal. 15, 1997, 1325–1333). Their objective was to develop a novel stationary phase that could be used to investigate the skin permeability coefficient of solutes (log K_p) in vitro. However, log k_KERATIN is not a sufficiently good predictor of skin permeability coefficient to be used as a sole descriptor in log K_p models. Turowski and Kaliszan reported that this descriptor can be used in combination with the chromatographic retention factor obtained by Immobilized Artificial Membrane Chromatography (log k_IAM) and the results of log K_p predictions using multiple linear regression (MLR) models are moderately satisfying. In this study, the values of log k_KERATIN obtained by Turowski and Kaliszan were correlated with a set of descriptors calculated using SwissADME software. It was discovered that log k_KERATIN encodes primarily lipophilicity, solubility, and molecular size descriptors, which are important factors governing the ability of compounds to cross the skin barrier. On the other hand, log k_KERATIN does not correlate with polar surface area (PSA) and the molecule’s ability to form hydrogen bonds—which are important properties in the context of solutes’ skin permeability. It was concluded that log k_KERATIN could be used as a descriptor in MLR models of log k_pin combination with other parameters, such as PSA or H-bond descriptors. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 205 KiB

Open AccessAbstract

BDDE-Inspired Chalcone Derivatives as New Antimicrobial Adjuvants

by Ana Jesus, Fernando Durães, Nikoletta Szemerédi, Joana Freitas-Silva, Paulo Martins Costa, Eugénia Pinto, Madalena Pinto, Gabriella Spengler, Emília Sousa and Honorina Cidade

Med. Sci. Forum 2022, 14(1), 68; https://doi.org/10.3390/ECMC2022-13650 - 16 Nov 2022

Viewed by 1211

Abstract

The effective response of antibiotics is threatened by the proliferation of micro-organisms that manifest resistance mechanisms, leading to an increase of progressively untreatable infectious diseases around the world. One solution to this problem could lie in shifting the strategy from searching for new [...] Read more.

The effective response of antibiotics is threatened by the proliferation of micro-organisms that manifest resistance mechanisms, leading to an increase of progressively untreatable infectious diseases around the world. One solution to this problem could lie in shifting the strategy from searching for new antibacterials to discovering new compounds that potentiate the antimicrobial activity of current antibiotics, therefore reverting resistance, through the interference with several mechanisms including biofilm formation and efflux pumps (EPs). Using bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) as a template, a macroalgae brominated bromophenol with antimicrobial activity, a series of 18 chalcone derivatives was prepared and evaluated for its antimicrobial activity and potential to fight antibiotic resistance. This includes seven chalcones, six dihydrochalcones and five diarylpropanes. Among them, two chalcones exhibited interesting antifungal activity and all compounds reversed resistance to vancomycin in the environmental isolate Enterococcus faecalis B3/101. Three compounds caused a four-fold decrease in the minimum inhibitory concentration (MIC) values of vancomycin against E. faecalis. All the dihydrochalcones and diarylpropanes displayed inhibition of EPs and biofilm formation in the tested multidrug-resistant strain, suggesting that these compounds are EP inhibitors. Notably, dihydrochalcones and diarylpropanes did not show cytotoxicity in a mouse embryonic fibroblast cell line and they can potentially be regarded as hits for bacterial EP inhibition. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 192 KiB

Open AccessAbstract

Development of Triazolyl Acetophenone Hybrids as a New Strategy for the Prevention of Marine Biofouling

by Daniela Pereira, Ana Rita Neves, Catarina Gonçalves, Vitor Vasconcelos, Madalena Pinto, Emília Sousa, Joana Reis de Almeida, Marta Correia-da-Silva and Honorina Cidade

Med. Sci. Forum 2022, 14(1), 69; https://doi.org/10.3390/ECMC2022-13430 - 1 Nov 2022

Viewed by 654

Abstract

The 1,2,3-triazole ring has been gaining increased attention in medicinal chemistry over the past few years since it has been associated with metabolic stability and several biological activities, including antifouling. Therefore, the hybridization of this heterocycle with other pharmacophores which showed ability to [...] Read more.

The 1,2,3-triazole ring has been gaining increased attention in medicinal chemistry over the past few years since it has been associated with metabolic stability and several biological activities, including antifouling. Therefore, the hybridization of this heterocycle with other pharmacophores which showed ability to prevent marine biofouling can be a strategy to obtain more effective and stable compounds. Marine biofouling remains a huge challenge for maritime industries and public health, causing economic, human, and ecological concerns, with few environmentally safe options to prevent this phenomenon. Considering that the incorporation of an acetophenone into coatings was found to decrease the attachment of marine micro- and macro-organisms, and in an attempt to obtain new effective acetophenone derivatives, a series of triazolyl acetophenones were obtained, through hybridization with the 1,2,3-triazole ring and other pharmacophores, using the copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) methodology. Fourteen new acetophenone-1,2,3-triazole hybrids were obtained and screening against the settlement of the macrofouling mussel Mytilus galloprovincialis and on five biofilm-forming marine bacteria allowed identifying promising compounds. Three compounds were able to inhibit the growth of marine bacteria Roseobacter litoralis, while the other three compounds significantly inhibited the settlement of mussel larvae. For those, the ability to inhibit the growth of Navicula sp. microalgae was also evaluated. One acetophenone was found to display complementary antifouling activity against macrofouling mussel and microalgae Navicula sp. The most potent compounds also were shown to be less toxic to the non-target species Artemia salina than the commercial biocide Econea^®. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 193 KiB

Open AccessAbstract

Molecular Dynamic Simulations-Based Conformational Analysis and Binding Study of CP-225917 on Farnesyl Transferase Enzyme

by Narayana Subbiah Hari Narayana Moorthy, Chandrabose Karthikeyan and Elangovan Manivannan

Med. Sci. Forum 2022, 14(1), 70; https://doi.org/10.3390/ECMC2022-13427 - 1 Nov 2022

Viewed by 567

Abstract

CP-225917 was isolated from unidentified fungi and exhibits farnesyl transferase and squalene synthase inhibitory activity. In the present investigation, computational studies including docking, molecular dynamic simulations, protein ligand interaction fingerprints (PLIF) analysis and pharmacokinetic properties calculations were performed on the molecule. The crystallographic [...] Read more.

CP-225917 was isolated from unidentified fungi and exhibits farnesyl transferase and squalene synthase inhibitory activity. In the present investigation, computational studies including docking, molecular dynamic simulations, protein ligand interaction fingerprints (PLIF) analysis and pharmacokinetic properties calculations were performed on the molecule. The crystallographic structure (pdb id 3E37) was used for the docking and MD simulation studies and it provided a docking score of −11.3 and FTase inhibitory activity of IC₅₀ = 6000 nM. Further, the conformational analysis studied the different conformations obtained from the MD simulations and PLIF analysis showed that the compound has significant interactions with Lys164, Tyr166, His201, ArgB202, HisB248, TyrB300, LysB356, TyrB361, HisB362 and ZnC1001 residues in the chain A and B of the FTase protein. However, the MD simulations revealed that the molecule has major interactions with the residues in the B chain of the FTase enzyme. The tyrosine residues TyrB300 and TyrB361 form surface and side-chain acceptor interactions and the TyrB361 residue has an interaction with the backbone acceptor and donor interactions. The histidine residues exhibited hydrogen bonding interactions and LysB356 has ionic interactions. The Zn metal showed ionic interaction with the ligand molecules for the activity. The Molecular Dynamics simulations of the complexes showed significant RMSD and RMSF values within the limit revealing that the complex is stabilized with these residues. These computational studies and the reported biological activities of the compound showed that this compound may be used as lead compounds to develop novel FTase inhibitors. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 216 KiB

Open AccessAbstract

Phytochemical and Bioactivity Studies from Plectranthus ecklonii^†

by Márcia Santos Filipe, Eva María Domínguez-Martín, Ana María Díaz-Lanza, Salvatore Princiotto and Patricia Rijo

Med. Sci. Forum 2022, 14(1), 71; https://doi.org/10.3390/ECMC2022-13431 - 1 Nov 2022

Viewed by 798

Abstract

Plectranthus is a well-known genus belonging to the Lamiaceae family and is mainly distributed in tropical areas of the globe. Furthermore, Plectranthus species are particularly rich in phenolic compounds and abietane-type diterpenes, such as royleanones, widely used in traditional medicine against a vast [...] Read more.

Plectranthus is a well-known genus belonging to the Lamiaceae family and is mainly distributed in tropical areas of the globe. Furthermore, Plectranthus species are particularly rich in phenolic compounds and abietane-type diterpenes, such as royleanones, widely used in traditional medicine against a vast range of diseases, including skin disorders and cancer. In order to study the phytochemical composition and the biological activity of P. ecklonii Benth., ultrasound-assisted extractions were carried out using methanol and acetone as solvents. It is known from the literature data that phenolic compounds are predominant in the methanol extracts, while the phytochemical analysis of the acetone extracts from our research group evidenced abietanes as the most frequently occurring secondary metabolites. Methanol extracts were screened to assay their potential bioactivity as antimicrobials, antioxidants, and on skin-related enzymes, as well as their general toxicity. The results showed only a moderate effect against bacteria, but a very promising antioxidant activity, and no relevant general toxicity. High tyrosinase inhibition was observed, together with an excellent inhibitory activity on collagenase, making the methanolic extract a promising raw material to be used for the development of dermo-cosmetic formulations, especially those with antiaging activity. Fractionation and further purification were carried out on the acetone extracts, highlighting a significant cytotoxic activity, mainly due to the presence of diterpenes, with an observed IC₅₀ in the low-micromolar range. Considering the potential applications for internal and topical uses, further studies are currently ongoing on both the extracts to investigate other relevant biological activities and ascertain their safety. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 179 KiB

Open AccessAbstract

Synthesis and Biological Evaluation of Novel 3-Isopropenyl-β-Lactams: Heterocyclic Bridged Analogues of Combretastatin A-4 as Novel Antimitotic Agents in Breast Cancer

by Azizah Malebari, Shu Wang and Mary J. Meegan

Med. Sci. Forum 2022, 14(1), 72; https://doi.org/10.3390/ECMC2022-13241 - 1 Nov 2022

Viewed by 632

Abstract

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. We have previously reported the synthesis of 3-vinyl-β-lactams (2-azetidinones) with potent antiproliferative activity against breast cancer MCF-7 cells. As a continuation of our research work on tubulin polymerization inhibitors, we now present [...] Read more.

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. We have previously reported the synthesis of 3-vinyl-β-lactams (2-azetidinones) with potent antiproliferative activity against breast cancer MCF-7 cells. As a continuation of our research work on tubulin polymerization inhibitors, we now present the synthesis and biochemical evaluation of a series of novel 3-isopropenyl-β-lactams (2-azetidinones) that are structurally related to the colchicine binding site tubulin inhibitor and vascular targeting agent, Combretastatin A-4. The 3-isopropenyl-β-lactams in this series contain 3,4,5-trimethoxyphenyl ring A (required for CA-4), together with selected ring B substituents. These compounds showed potent activity against breast cancer in MCF-7 and triple negative MDA-MB-231 breast cancer cells and are minimally toxic to non-tumorigenic human embryonic kidney HEK-293T cells. Moreover, the compounds significantly arrested cell division during the G2/M phase and induced apoptosis in the MCF-7 cell line. Immunofluorescence studies in MCF-7 cells showed that the 3-isopropenyl-β-lactam caused mitotic catastrophe by targeting tubulin and inhibited tubulin polymerization. In conclusion, the 3-isopropenyl-2-azetidinones could be promising lead compounds for the development of anti-breast cancer drugs that target tubulin in future clinical trials. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 162 KiB

Open AccessAbstract

Effects of Protein Hydrophobicity on Protein Corona Formation Modes on Soluplus^® Nanomicelles

by Wenhao Wang, Ziqiao Zhong, Zhengwei Huang, Ying Huang, Chuanbin Wu and Xin Pan

Med. Sci. Forum 2022, 14(1), 73; https://doi.org/10.3390/ECMC2022-12866 - 2 Aug 2022

Viewed by 627

Abstract

Soluplus^® nanomicelles are increasingly recognized as excellent drug carriers due to their great drug loading capacity. Nevertheless, the protein corona would form when it was subjected to biological fluids, but a few efforts have been made to elucidate this. Here, the effects [...] Read more.

Soluplus^® nanomicelles are increasingly recognized as excellent drug carriers due to their great drug loading capacity. Nevertheless, the protein corona would form when it was subjected to biological fluids, but a few efforts have been made to elucidate this. Here, the effects of protein hydrophilicity on protein corona formation modes were investigated based on three model proteins, bovine serum albumin (BSA, which is hydrophilic), lysozyme (Lyso, which is hydrophilic) and bovine hemoglobin (BHb, which is more hydrophobic). Protein corona formation was proved by the size and zeta potential measurements, while the size increments of the BHb group were the most significant ones. We hypothesized that the hydrophilic protein might be dominated by the surface adsorption mode, where the proteins were cross-linked by the outer layer polyethylene glycol (PEG) chains. However, the hydrophobic protein may show an insertion mode, where the nonpolar part is inserted into the hydrophobic core of nanomicelles and the polar part is distributed on the surface. To justify this hypothesis, the microenvironment polarity of hydrophobic tryptophan (Trp) acid amino residue was analyzed. The most obvious peak wavelength changed, and the minute absorbance changes were exhibited in ultraviolet-visible spectra of the BHb group, indicating that the hydrophobic Trp was distributed in the nonpolarity core of nanomicelles. This conclusion was further proved by similar results in the fluorescence emission wavelength. In addition, the circular dichroism results confirm the obvious arresting conformational changes induced by the insertion mode protein corona formation. In summary, the hydrophilic proteins follow the surface adsorption mode, while the hydrophobic proteins follow the insertion mode in the protein corona formation of Soluplus^® nanomicelles. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 197 KiB

Open AccessAbstract

Development of New Anti-Virulence Agents to Tackle Multi-Resistant Pseudomonas aeruginosa

by Marie Hanot, Elodie Lohou and Pascal Sonnet

Med. Sci. Forum 2022, 14(1), 74; https://doi.org/10.3390/ECMC2022-13428 - 1 Nov 2022

Viewed by 679

Abstract

The multi-resistant opportunistic bacterium Pseudomonas aeruginosa has been identified by the WHO as one of the most threatening pathogens of our time and a priority for the development of new treatments. The biofilms produced by this micro-organism act as protective barriers. They increase [...] Read more.

The multi-resistant opportunistic bacterium Pseudomonas aeruginosa has been identified by the WHO as one of the most threatening pathogens of our time and a priority for the development of new treatments. The biofilms produced by this micro-organism act as protective barriers. They increase its pathogenicity via a persistence towards the immune system and its resistance to antibiotics. Biofilm formation is coordinated by Quorum Sensing (QS), which is a bacterial communication network responsible for virulence pathways expression according to the population density. In P. aeruginosa-specific QS system pqs, the transcription factor PqsR regulates the activation of virulence-related genes via the recognition of its auto-inducer PQS (Pseudomonas Quinolone Signal). This circuit stimulates the secretion of virulence factors, such as pyocyanin, and the establishment of biofilms. Therefore, the development of non-bactericidal agents that disrupt QS connections appears to be a promising alternative to conventional medicines without creating selection pressure issues. These new anti-virulence agents (AVAs) could restore the efficacy of antibiotics when used in combination therapy. In particular, the design of AVAs that inhibit PqsR appears to be a sustainable approach to specifically combat P. aeruginosa. Bi-aromatic PqsR inhibitors possessing a 4-aminoquinoline moiety have been described in the literature. Moreover, our team recently discovered a series of 2-heteroaryl-4-quinolones that display interesting anti-biofilm and anti-pyocyanin activities. We now aim to develop a family of 2-heteroaryl-4-aminoquinolines as new AVAs that can potentially inhibit PqsR. The synthesis and the physicochemical and biological evaluation of those novel molecules will be described in the poster. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 200 KiB

Open AccessAbstract

In Silico Fragment-Based Drug Design and Molecular Docking of Tranilast Analogues as Potential Inhibitors of Transforming Growth Factor- β Receptor Type 1

by Nusaiba A. Babiker, Ahmed T. Negmeldin and Eman M. El-labbad

Med. Sci. Forum 2022, 14(1), 75; https://doi.org/10.3390/ECMC2022-13472 - 1 Nov 2022

Viewed by 799

Abstract

Transforming Growth Factor- β Receptor type 1 (TGF-βR1) is an important anticancer target involved in promoting cell proliferation, progression, and metastasis through the induction of angiogenesis and suppression of immunological responses during the late stage of malignancy. Tranilast was initially approved for the [...] Read more.

Transforming Growth Factor- β Receptor type 1 (TGF-βR1) is an important anticancer target involved in promoting cell proliferation, progression, and metastasis through the induction of angiogenesis and suppression of immunological responses during the late stage of malignancy. Tranilast was initially approved for the treatment of bronchial asthma and allergic conditions in 1982. Later, it was revealed that Tranilast had numerous effects on cancer hallmarks, including immune evasion and sustained proliferation via the inhibition of TGF-βR1. This research describes the design of a novel series of anthranilate derivatives having various modes of interactions with TGF-βR1 compared with Tranilast. A database of novel Tranilast analogues was generated using Molecular Operating Environment Software (MOE 2020.09, Chemical Computing Group CCG, Montréal, Canada) using fragment-based drug design. Representative compounds were selected from the database and docked in the identified binding site of TGF-βR1. Several compounds showed higher binding affinity for TGF-βR1 compared with the lead compound in this work, Tranilast. Compounds with high docking scores contained a positively charged amine group that interacted with Asp290 or a negatively charged carboxylate group with Lys 335 in the TGF-βR1 ATP binding site. Additionally, compounds containing an aromatic group showed high docking scores through interacting with Ser287, Lys337, or Ile 211. Compounds A11, A14, A16, and B5 which had the best poses in terms of binding interactions and docking scores to the binding site will be considered for further synthesis and biological evaluation. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 184 KiB

Open AccessAbstract

Bezoar: The Stone of the Guanaco

by Juan Beltramino, Marcela Villalba, Agostina Casimiro and Vanina Pereyra

Med. Sci. Forum 2022, 14(1), 76; https://doi.org/10.3390/ECMC2022-13303 - 1 Nov 2022

Viewed by 900

Abstract

This research work allowed the development of a scientific approach to a remedy widely used until today in ranches or rural posts as an alternative medicine: the “guanaco stone” or bezoar. Bezoars are compactions of various chemical substances, hairs, vegetable fibers and foreign [...] Read more.

This research work allowed the development of a scientific approach to a remedy widely used until today in ranches or rural posts as an alternative medicine: the “guanaco stone” or bezoar. Bezoars are compactions of various chemical substances, hairs, vegetable fibers and foreign bodies, which are formed mainly between the divisions of the stomach of guanacos (Lama guanicoe). The ethnomedicine of this Patagonian region uses powdered bezoars ingested with water or in infusions, as a medicine that improves digestive and renal functions, and especially alexipharmaceuticals. The objective of this trial was to find “in vitro” the pharmacological foundations of bezoars. Samples of bezoars, obtained from the local refrigerator, were used in the test. For this, their density, colors, and hardness were determined. One of the bezoars was totally pulverized, the powder obtained was observed under an optical microscope with a magnification of 1000×. Subsequently, the chemical composition was sought by examining the presence of P, K, and N, as well as the pH. The results made it possible to determine the pH was neutral and the presence of P, N, and K was medium. It is concluded in this first approach to the subject that according to these determinations, bezoars can act via two mechanisms: the presence of phosphates acts as chelators of ingested toxins, facilitating their elimination from the body, but also the minerals that together stimulate the secretion of acid gastric and digestive enzymes. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 191 KiB

Open AccessAbstract

Assessment of Natural Hydroxycinnamic Acid Derivatives for Their Potential as Antimicrobial and Antioxidant Agents

by Mala M. Parab, Tanmay Arekar, Viraj J. Sadrani, Priyanshu P. Gupta, Debjani Dasgupta and Pramodkumar P. Gupta

Med. Sci. Forum 2022, 14(1), 77; https://doi.org/10.3390/ECMC2022-13503 - 8 Nov 2022

Viewed by 1287

Abstract

Nutraceuticals are a category of treatments which have gained more attention from people in recent times. Dietary polyphenols, as nutraceutical products, constitute two groups. Hydroxycinnamic acids are one of those two groups. These acids are found naturally in various products we consume on [...] Read more.

Nutraceuticals are a category of treatments which have gained more attention from people in recent times. Dietary polyphenols, as nutraceutical products, constitute two groups. Hydroxycinnamic acids are one of those two groups. These acids are found naturally in various products we consume on a day-to-day basis. Coffee is one of the most common sources of hydroxycinnamic acids. Cinnamon is a spice that is consumed in different forms in various food products. The study presented investigates their capacity as antioxidant agents and anti-microbial agents through in-vitro and in silico approaches. For this, commonly found infectious organisms namely, E. coli, S. aureus, K. pneumoniae, and S. pyogenes were cultured. The minimum inhibitory concentrations for methanolic coffee extract as well as methanolic cinnamon extract were estimated to be ~0.4 μg/mL and ~5 μg/mL. The cytotoxicity effects of these extracts were studied on cell line MCF-7 (human breast cancer cell line). IC50 values for MCF-7 were calculated at 64.04 μg/mL for coffee extract, 81.12 μg/mL for cinnamon extract, and 51.14 μg/mL for standard caffeic acid. Molecular docking analysis revealed the efficiency of different hydroxycinnamic acids on protein receptors, namely PPAR, IL-6, TNF- alpha, and VEGF. These results were supported by the tests performed on blood cultures and human tissue samples obtained from the clinical partner. The present study endeavors to set a preliminary platform for understanding the efficiency and efficacy of hydroxycinnamic acid derivatives in commonly used food sources. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 175 KiB

Open AccessAbstract

On the Bibliometric Profile of Metered Dose Inhaler Research

by Lei Shu, Zhengwei Huang, Ying Huang, Chuanbin Wu and Xin Pan

Med. Sci. Forum 2022, 14(1), 78; https://doi.org/10.3390/ECMC2022-12908 - 19 Sep 2022

Viewed by 622

Abstract

Pulmonary drug delivery systems (PDDS) have gained particular attention of pharmaceutical scientists due to their potency in the therapy of both pulmonary diseases and systemic diseases. Metered dose inhalers (MDI) as a delivery approach of PDDS have ample advantages over other approaches. No [...] Read more.

Pulmonary drug delivery systems (PDDS) have gained particular attention of pharmaceutical scientists due to their potency in the therapy of both pulmonary diseases and systemic diseases. Metered dose inhalers (MDI) as a delivery approach of PDDS have ample advantages over other approaches. No drying process is associated with MDI, which avoids the chemical and physical instability. MDI are cost-effective, portable and can be self-administered. It was recently reported that MDI have occupied a large proportion of the respiratory drug market since the last century. To facilitate the future studies on MDI, this work was aimed at conducting bibliometric analysis of the publications of MDI in Science Citation Index Expanded database of Web of Science from 2000 to 2020 (2858 in total). The documents were processed by Clarivate Analytic tool equipped by Web of Science, VOSviewer, Statistical Analysis Toolkit for Informetric (SATI) and bibliometric online platform, and the data were visualized. After describing the detailed bibliometric profile of MDI publications, which included publication years, countries/regions, organizations, research areas, publication media, authorship and funding agencies, we assessed the publication tendencies by virtue of analysis of co-citation, bibliographic coupling, keywords and co-occurrence. Based on the results, we put forward three promising topics for future studies of MDI. Taken together, we believe that MDI became a topic under investigation around the world, and will still be important for fundamental and translational researches. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 211 KiB

Open AccessAbstract

Metabolism of Cathinones in Functional Hepatocyte-like Cells Derived from Human Neonatal Mesenchymal Stem Cells: An Enantioselectivity Approach

by Barbara Silva, Joana Saraiva Rodrigues, Joana Paiva Miranda, Ana Sofia Almeida, Carla Fernandes, Paula Guedes de Pinho and Fernando Remião

Med. Sci. Forum 2022, 14(1), 79; https://doi.org/10.3390/ECMC2022-13302 - 1 Nov 2022

Viewed by 625

Abstract

Liver damage is a common issue associated with synthetic cathinones abuse. Indeed, human stem cell-derived hepatocyte-like cells (HLCs) have been used as alternative in vitro models for hepatotoxicity studies, due to their ability to maintain a stable hepatic-specific phenotype. Furthermore, all cathinone derivatives [...] Read more.

Liver damage is a common issue associated with synthetic cathinones abuse. Indeed, human stem cell-derived hepatocyte-like cells (HLCs) have been used as alternative in vitro models for hepatotoxicity studies, due to their ability to maintain a stable hepatic-specific phenotype. Furthermore, all cathinone derivatives are chiral, and their biological effects can differ for each enantiomer. Thus, the aim of this work was to evaluate the cytotoxicity and metabolism of pentedrone and methylone enantiomers using HLC models. Human neonatal mesenchymal stem cells were differentiated into HLCs by a three-step differentiation protocol and maintained under 2D and 3D culture conditions. Subsequently, pentedrone and methylone enantiomers were isolated by HPLC using a chiral stationary phase. Cell viability was evaluated through the CellTiter-Glo assay and the formation of methylone and pentedrone metabolites was analyzed by GS-MS. The racemates of pentedrone and methylone exhibited potential hepatotoxicity in a concentration-dependent manner in both models. Different cytotoxic profiles for pentedrone enantiomers were observed in HLC 3D, with R-(-)-pentedrone being the most cytotoxic. Concerning HLC 2D metabolic assays, S-(-)-methylone was preferentially metabolized via N-demethylation, whereas R-(+)-methylone was metabolized by O-demethylation and N-hydroxylation. However, in HLC 3D assays, R-(+)-methylone was preferentially metabolized by all metabolic pathways, except for O-demethylation. Regarding pentedrone enantiomers, the metabolic pathways studied were more pronounced for R-(-)-pentedrone, namely N-demethylation and β-keto reduction in both models. Overall, this study revealed stereoselectivity in cytotoxicity and metabolism pathways for pentedrone and methylone. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 164 KiB

Open AccessAbstract

4’4 Bromophenyl 4’Piperidinol Derivatives as a Multifactorial Anti-Alzheimer Agent: Synthesis, In-Vitro, and In-Silico Based Studies

by Syeda Abiha Rizvi, Nousheen Mushtaq, Ahsaan Ahmad, Laila Anwer, Saira Asghar, Mariam Arefa, Anam Zehra, Madiha Arif and Farah Batool

Med. Sci. Forum 2022, 14(1), 80; https://doi.org/10.3390/ECMC2022-13265 - 1 Nov 2022

Viewed by 772

Abstract

4’4 bromophenyl 4’piperidinol derivatives were synthesized, and evaluated as multifactorial agents for the treatment of Alzheimer’s disease (AD). Among all the analogues, AB11 and AB14 showed the best activity against acetylcholinesterase (AChE) with IC₅₀ = 0.029 μM and 0.038 μM, respectively. Both [...] Read more.

4’4 bromophenyl 4’piperidinol derivatives were synthesized, and evaluated as multifactorial agents for the treatment of Alzheimer’s disease (AD). Among all the analogues, AB11 and AB14 showed the best activity against acetylcholinesterase (AChE) with IC₅₀ = 0.029 μM and 0.038 μM, respectively. Both compounds also acted as a good antioxidant agent (IC₅₀ = 26.38 μM for AB11 and 23.99 μM for AB14), while AB11 is the only molecule that displayed moderate inhibition of amyloid beta (Aβ) (43.25% at 500 μM). AB11 and AB14 were found selective against monoamine oxidase-B (MAO-B) with IC₅₀ values of 866 μM and 763 μM, respectively. AB10, AB17, and AB70 exhibited activity against both MAO-A and MAO-B and showed inhibitory potential against acetylcholinesterase; moreover, all analogues are capable of disassembling the well-structured Aβ fibril. Molecular modeling of selected compounds displayed interactions with the active site of human MAO-B and AChE enzyme. The results suggested that AB11 is a promising multi-target hit that can be optimized further as a successful drug molecule for the treatment of AD. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 196 KiB

Open AccessAbstract

Anti-Inflammatory Evaluation of Ukrainian Herbal Extracts

by Olha Mykhailenko, Michal Korinek, Kateryna Uminska, Mohamed El-Shazly, Liudas Ivanauskas, Fang-Rong Chang, Victoriya Georgiyants and Tsong-Long Hwang

Med. Sci. Forum 2022, 14(1), 81; https://doi.org/10.3390/ECMC2022-13651 - 16 Nov 2022

Viewed by 1223

Abstract

Neutrophils play a crucial role in providing protection against intracellular pathogens, such as viruses and mycobacteria, but also in regulating systemic anaphylaxis or allergic skin reactions. Neutrophils intimately shape the adaptive immune response at various levels, including the B cells, dendritic cells, and [...] Read more.

Neutrophils play a crucial role in providing protection against intracellular pathogens, such as viruses and mycobacteria, but also in regulating systemic anaphylaxis or allergic skin reactions. Neutrophils intimately shape the adaptive immune response at various levels, including the B cells, dendritic cells, and T cell populations. In pharmacy, significant attention is given to the search for natural substances that can affect the immune system and neutrophil function with less adverse side effects. The phytoconstituents, such as polysaccharides, polyphenols, or terpenes, may serve as good candidates. Previously, we evaluated the anti-inflammatory activities of various plant extracts of the Iridaceae family and identified extracts of Iris spp. rhizomes and Crocus sativum corms as promising anti-neutrophilic agents. The current study further extends this analysis of various groups of biologically active substances found in extracts from Ukrainian plants. The tested samples include polysaccharide complexes of Crocus flowers and corms, Juno leaves and corms, Iris leaves and rhizomes, and Chamaenerion leaves, as well as water and ethanolic extracts from Chamaenerion leaves. Using fMLF/CB-induced superoxide anion generation and elastase release assays applied to human neutrophils, the C. angustifolium ethanolic (50%, vol/vol) and water extracts almost completely inhibited the fMLF/CB-induced elastase release at 10 μg/mL (IC₅₀ 2.8–4.1 μg/mL). Interestingly, the Iris leaf polysaccharide extract also inhibited elastase release by 39.0% (10 μg/mL), while the C. angustifolium polysaccharides extract inhibited the superoxide by 45.5% (10 μg/mL). This suggests that phenolic compounds may possess a better activity in comparison with polysaccharides. The present study provided primary pharmacological evidence for anti-inflammatory agents derived from C. angustifolium. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Hybridization of Fluoroquinolones as a Promising Pathway towards New Antibiotics

by Halyna Hryhoriv, Sergiy M. Kovalenko, Lyudmila Sidorenko, Natalia Filimonova, Lina Perekhoda and Victoriya Georgiyants

Med. Sci. Forum 2022, 14(1), 82; https://doi.org/10.3390/ECMC2022-13145 - 1 Nov 2022

Viewed by 595

Abstract

The current situation in medicine and pharmacy still requires the time and effort of medicinal chemists, who must develop new synthetic approaches and create promising molecules that can turn into novel antimicrobials. Due to the problem of resistance to well-known antibiotics combined with [...] Read more.

The current situation in medicine and pharmacy still requires the time and effort of medicinal chemists, who must develop new synthetic approaches and create promising molecules that can turn into novel antimicrobials. Due to the problem of resistance to well-known antibiotics combined with the occurrence of new diseases that we observe, we can be sure that this research is going to be in demand. However, not always searching for a totally new molecule seems to be a good idea. The structural modification and hybridization of once efficient agents is also logical and actually has already provided us with many generations of antibiotics. Therefore, our scientific team has been working with fluoroquinolones with the aim of conducting docking studies, modifying them, and then studying the biological activity of the obtained compounds. In the first stage of the research, we conducted docking studies and then started to work on ciprofloxacin and norfloxacin, only modifying their C-7 position. The introduction of a 1,2,3-triazole moiety as a result of a convenient synthetic procedure led to new molecules for which moderate antimicrobial and antifungal activities were revealed. Furthermore, the C-3 position was modified with an arylsulfonyl moiety with parallel modifications of N-1 and C-7. For now, synthetic procedures have been developed for the similar transformation and biological activity of the obtained compounds that are under study. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 197 KiB

Open AccessAbstract

Impact of Chenopodium album and Allium sativum Extracts Alone and in Combination against Mastitogens

by Noor Ul Absar, Rabia Tanvir, Noreen Sarwar and Qamar Un Nisa

Med. Sci. Forum 2022, 14(1), 83; https://doi.org/10.3390/ECMC2022-13168 - 1 Nov 2022

Viewed by 587

Abstract

In the dairy sector, mastitis is one of the most important and costly diseases because, due to it, the world’s economy faces about 35 billion dollar loss each year. Bacterial pathogens that cause mastitis are called mastitogens. Among these bacterial species, Escherichia coli [...] Read more.

In the dairy sector, mastitis is one of the most important and costly diseases because, due to it, the world’s economy faces about 35 billion dollar loss each year. Bacterial pathogens that cause mastitis are called mastitogens. Among these bacterial species, Escherichia coli, Staphylococcus aureus, Streptococcus uberis, Streptococcus agalactia, and Streptococcus dysgalactia are the most important. Mastitis is treated with antibiotics; however, due to their improper, excessive, and irrational usage, these pathogens have become resistant to them. Drug residues in milk is also a factor resulting in multi-drug resistance (MDR) in mastitogens that cause treatment to become ineffective. In Pakistan, several ethnoveterinary plants, such as Allium sativum (garlic) and Chenopodium album (goosefoot), are used for the treatment of mastitis in cattle and buffalo. For this purpose, we prepared aqueous and methanol extracts of A. sativum and C. album. In the agar well diffusion method, the aqueous A. sativum showed strong activity against Staphylococcus aureus, i.e., 20 mm, whereas the methanolic extract of C. album gave an 11 mm zone of inhibition against Staphylococcus aureus. By combining the extracts of A. sativum and C. album, they give a synergistic effect, especially against E. coli. Results showed that the zone of inhibition against Staphylococcus aureus was 16 mm, against E. coli was 22 mm, and against Streptococcus uberis was 5 mm. Our study is in agreement with the use of A. sativum and C. album in cases of mastitis and recommends their combined use for better results. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 194 KiB

Open AccessAbstract

Dynamic Cross-Correlation Matrix (DCCM) Reveals New Insights to Discover New NLRP3 Inhibitors Useful as Anti-Inflammatory Drugs

by Igor José dos Santos Nascimento, Marianny De Souza, Daniel Calazans Medeiros and Ricardo Olimpio de Moura

Med. Sci. Forum 2022, 14(1), 84; https://doi.org/10.3390/ECMC2022-13306 - 1 Nov 2022

Cited by 3 | Viewed by 1680

Abstract

The innate immune system is responsible for the body’s defense against aggressive agents, mainly through activating pattern-recognition receptors (PRRs). Recognizing these agents results in an inflammatory response that activates tissue repair and eliminates the agent. Among the macromolecules related to these events are [...] Read more.

The innate immune system is responsible for the body’s defense against aggressive agents, mainly through activating pattern-recognition receptors (PRRs). Recognizing these agents results in an inflammatory response that activates tissue repair and eliminates the agent. Among the macromolecules related to these events are inflammasomes (inflammatory response activators), with emphasis on nucleotide-binding domain leucine-rich repeat-containing receptors protein 3 (NLRP3), in which blocking their oligomerization inhibits inflammasome activity. In this way, targeting NLRP3 represents a new approach to designing anti-inflammatory drugs. Here, molecular docking and dynamics, focusing on Dynamic Cross-Correlation Matrix (DCCM) analysis, were used to characterize the significant interactions of MCC950 (known inhibitors) and their analog NP3-166 (ligand co-crystalized) with NLRP3 and generate useful information in drug design. The results showed that the compounds were stable during the MD simulation time (100 ns), demonstrated by the RMSD RMSF, R_g, SASA, and H-bond plots. Analysis of the DCCM graphs showed that more correlated movements are present for MCC950 compared to NP3-166. In fact, the more rigid structure of MCC950 may influence the more significant interaction. A higher correlation observed in both complexes between residues 100–200 and 300–400 highlights the results obtained from the interaction analysis, showing that interaction with Ala²²⁸ and Arg⁵⁷⁸ may be essential for the inhibitory activity of the compounds. Our findings highlight that greater structural rigidity of the ligand and interactions with residues Ala²²⁸ and Arg⁵⁷⁸ may be critical for designing new NLRP3 inhibitors with anti-inflammatory potential. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 201 KiB

Open AccessAbstract

Cu(PPh₃)₃Br-Catalyzed Synthesis of New Paracetamol–1,2,3-Triazole Molecular Hybrids from Expired Commercial Tablets and Their In Silico Assessment to Study Their Pharmacological Properties

by Daniela Calderón Lamus, Carlos Eduardo Puerto Galvis and Vladimir Kouznetsov

Med. Sci. Forum 2022, 14(1), 85; https://doi.org/10.3390/ECMC2022-13238 - 1 Nov 2022

Viewed by 886

Abstract

The 1,2,3-Triazole ring has remarkable importance in medicinal chemistry due to its unique biological properties, such as metabolic stability and ability to form hydrogen bonds. Several biological activities had been reported for this structural nucleus, while paracetamol (acetaminophen) or N-(4-hydroxyphenyl)acetamide) is one [...] Read more.

The 1,2,3-Triazole ring has remarkable importance in medicinal chemistry due to its unique biological properties, such as metabolic stability and ability to form hydrogen bonds. Several biological activities had been reported for this structural nucleus, while paracetamol (acetaminophen) or N-(4-hydroxyphenyl)acetamide) is one of the most popular and widely used drugs for the treatment of pain and fever. By applying a molecular hybridization strategy, numerous 1,2,3-triazole-based compounds have been designed, prepared, and studied for pharmacological applications in multiple laboratories around the world. Considering this context, we used expired acetaminophen pills as the starting material for generating new series of functionalized paracetamol–1,2,3-triazole hybrids. Their synthesis consisted of a Cu(PPh₃)₃Br-catalyzed 1,3-dipolar cycloaddition reaction of the O-propargyl-acetaminophen and several azides prepared from commercially available anilines, following the protocol reported by Filimonov et al. By performing click chemistry and considering green chemistry principles, interesting paracetamol–1,2,3-triazole derivatives were easily prepared in 64–93% yields. Obtained hybrids were subjected to an in silico analysis (Molinspiration, OSIRIS, and DRUDIT), evaluating some physicochemical properties and toxicity risks. According to the predicted biological properties, most of the prepared hybrid molecules exhibited adequate parameters as potential pharmacological agents, presenting high inhibitory activity, low risks of toxicity, and good affinity for various biological targets. This work highlights the recycling of expired drugs and accessibility to new paracetamol-based compounds under green mild reaction conditions (H₂O/tert-BuOH mixture, rt) and low catalytic loads (1 mol% Cu(PPh₃)₃Br). Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 172 KiB

Open AccessAbstract

The Effects of Gold Nano Sensitiser Photodynamic Therapy on the Proliferation, Invasion, and Migration of Lung Cancer Stem Cells

by Anine Crous and Heidi Abrahamse

Med. Sci. Forum 2022, 14(1), 86; https://doi.org/10.3390/ECMC2022-13185 - 1 Nov 2022

Viewed by 736

Abstract

Lung cancer relapse and post-treatment dissemination suggest the presence of drug resistant populations of cells called cancer stem cells (CSCs). Cancer metastases and the risk of secondary tumours are the most frequent causes of mortality in many cases. One important feature of lung [...] Read more.

Lung cancer relapse and post-treatment dissemination suggest the presence of drug resistant populations of cells called cancer stem cells (CSCs). Cancer metastases and the risk of secondary tumours are the most frequent causes of mortality in many cases. One important feature of lung cancer prognosis is metastases and the invasive ability of the cells, which is driven by CSCs. Considering CSC proliferation and migration associated with metastases, therapeutic strategies targeting these CSCs are considered to improve long-term clinical outcome. A minimally invasive, clinically approved cancer treatment, Photodynamic therapy (PDT), along with the use of a nano drug carrier was used in this study. PDT is based on the principle of light stimulation of a photosensitising drug that induces tumour cell death. Nano-mediated PDT using gold nanoparticles has been seen to induce cell death in lung CSCs. In this study, morphological examination and various physiological experiments including migration, proliferation, cytotoxicity, population doubling time, and cell cycle analysis assay were conducted to determine whether PDT using a gold nano sensitiser prevents CSC migration and invasion. Results show that the use of nanoPDT, using a AlPcS₄Cl and AuNPs conjugate, can inhibit CSC migration and invasion, induce cell cycle arrest, and decrease CSC proliferative abilities. The use of a drug nano carrier in the form of AuNPs can improve the effectivity of PDT cancer treatment, and specifically facilitate the inhibition of metastasis seen in lung cancer caused by CSCs, which can clinically relate to an improved prognosis. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 195 KiB

Open AccessAbstract

High-Capacity CaCO₃ Containers: The Effect of Size on Drug Loading and Interaction with Cells

by Tatiana Pallaeva, Alexander Mikheev, Daniil Eurov, Dmitry Kurdyukov, Victoriya Popova, Elena Dmitrienko, Roman Akasov and Daria Trushina

Med. Sci. Forum 2022, 14(1), 87; https://doi.org/10.3390/ECMC2022-13496 - 7 Nov 2022

Viewed by 1217

Abstract

A series of calcium carbonate particles with sizes of 500 ± 80 and 200 ± 90 nm were obtained using mass crystallization in aqueous salt solutions by varying the reaction conditions and adding glycerol or a combination of polyethylene glycol, polysorbat-80 and cell [...] Read more.

A series of calcium carbonate particles with sizes of 500 ± 80 and 200 ± 90 nm were obtained using mass crystallization in aqueous salt solutions by varying the reaction conditions and adding glycerol or a combination of polyethylene glycol, polysorbat-80 and cell cultural medium to the reaction volume. Calcium carbonate nanoparticles of 50 ± 30 nm in diameter were synthesized within the pores of mesoporous silica particles with a subsequent etching out of the template material. A complete characterization of the particles was carried out using scanning and transmission electron microscopy, X-ray powder diffraction, and dynamic and electrophoretic light scattering. CaCO₃ particles were loaded with anticancer drugs, porphyrazine and doxorubicin, with an encapsulation efficiency of 2–5 and 4–11 wt.%, respectively. The spontaneous release at pH 7 reached 15%, and when the particles are dissolved at pH 4, the release was about 45% of the substance during the day, regardless of the encapsulated substance. Functionalization of the surface of calcium carbonate particles with a biocompatible Pluronic-folic acid conjugate did not affect the particle size distribution and aggregative stability for all three samples. The effect of coatings on the rate of internalization and accumulation of particles by cells expressing folic acid receptors was established. It was also shown that the internalization of 50 ± 30 nm particles was more active than other samples. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 202 KiB

Open AccessAbstract

Design, Synthesis and Antimicrobial Activities of Quinoline-Based FabZ Inhibitors as Promising Antimicrobial Drugs

by Laurie Bibens, Jean-Paul Becker, Nadine Lemaitre, François Peltier, Virginie Morel, Céline Damiani, Nicolas Taudon, Alexandra Dassonville-Klimpt and Pascal Sonnet

Med. Sci. Forum 2022, 14(1), 88; https://doi.org/10.3390/ECMC2022-13165 - 1 Nov 2022

Viewed by 580

Abstract

At present, antimicrobial resistance is one of the most significant public health challenges [...] Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Prodrugs Activated by Vascular Ectopeptidases: Proof of Concept

by François Marceau

Med. Sci. Forum 2022, 14(1), 89; https://doi.org/10.3390/ECMC2022-12906 - 19 Sep 2022

Viewed by 616

Abstract

Several vascular ectopeptidases reside in blood vessels and efficiently regulate peptide hormones. For instance, bradykinin (BK) is inactivated by angiotensin converting enzyme (ACE) or arginine-carboxypeptidases (Arg-CPs), and aminopeptidase N (APN) cleaves several substrates. Whether such peptidases may activate latent prodrugs of vasoactive agents [...] Read more.

Several vascular ectopeptidases reside in blood vessels and efficiently regulate peptide hormones. For instance, bradykinin (BK) is inactivated by angiotensin converting enzyme (ACE) or arginine-carboxypeptidases (Arg-CPs), and aminopeptidase N (APN) cleaves several substrates. Whether such peptidases may activate latent prodrugs of vasoactive agents has been tested. The contractility of the isolated human umbilical vein, radioligand binding assays, immunolocalization of peptidases, the internalization cycle of fluorescent receptors (microscopy), blood pressure measurements in anesthetized rats, and specific inhibitors of peptidases have been exploited to show the feasibility of prodrug activation by vascular peptidases. L-alanyl-histamine has virtually no affinity for the human histamine H1 receptor, but releases histamine and contracts the vein following cleavage by endogenous APN. Prolonged sequences of BK, such as BK-Arg, Arg⁰-BK-Arg-Arg, and BK-His-Leu have little affinity for the BK B2 receptor, but are contractile in the umbilical vein and hypotensive in anesthetized rats via their action on this receptor type following cleavage of the C-terminal extensions by Arg-CPs for the first two peptides, as well as by ACE for the last two. Vascular ectopeptidases were shown to activate latent agonists of the H1 and B2 receptors, a concept that could be extended to various classes of drugs for a local action on the vasculature. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 187 KiB

Open AccessAbstract

Single Domain Magnetic Nanoparticles as Magneto-Mechanical Actuators for Remote Drug Release from Polyelectrolyte Microcapsules

by Ivan Burmistrov, Maxim Veselov, Alexander Mikheev, Tatiana Pallaeva, Tatiana Bukreeva, Natalia Klyachko and Daria Trushina

Med. Sci. Forum 2022, 14(1), 90; https://doi.org/10.3390/ECMC2022-13495 - 7 Nov 2022

Viewed by 1148

Abstract

The modification of capsule shells with synthesized magnetic iron oxide nanoparticles aims not only to control the localization of capsules, but also to tune their permeability. The application of a super low frequency non-heating magnetic field (100 Hz) for these purposes offers prospects [...] Read more.

The modification of capsule shells with synthesized magnetic iron oxide nanoparticles aims not only to control the localization of capsules, but also to tune their permeability. The application of a super low frequency non-heating magnetic field (100 Hz) for these purposes offers prospects for high penetration ability into tissues, high locality, and safety, which makes this method preferable for use with in vivo rather than magnetic hyperthermia. In this work, we develop a proof of concept for the remotely controlled release of an encapsulated drug from polyelectrolyte microcapsules under exposure to an alternating super low frequency magnetic field. The characteristics of the tailor-made nanoparticles for the polyelectrolyte shell modification were analyzed to confirm their perspectives as magneto-mechanical actuators due to their abilities with the Brownian relaxation. Polyelectrolyte microcapsules were obtained using the well-known method of sequential deposition of polyelectrolytes on the surface of vaterite particles. We studied the time dependence of the amount of released fluorescently labeled high-molecular weight substance on the frequency of the applied magnetic field (100 mT, 20–100 Hz) and demonstrated that the application of a magnetic field with a frequency of 50 Hz leads to the most pronounced selective increase in the permeability of the shells. Our findings provide a promising application of composite magnetic microcapsules with permeability triggered by a super low frequency magnetic field for the controlled release of drugs without dangerous heating or overheating of the biological tissues. This work was supported by the grant of the President of the Russian Federation (MK-1109.2021.1.3). Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

MARSplines Approach for Quantitative Relationships between Structure and Pharmacological Activity of Potential Drug Candidates

by Marcin Gackowski, Karolina Szewczyk-Golec and Marcin Koba

Med. Sci. Forum 2022, 14(1), 91; https://doi.org/10.3390/ECMC2022-13170 - 1 Nov 2022

Viewed by 628

Abstract

A multivariate adaptive regression splines (MARSplines) approach was applied to the quantitative structure–activity relationship studies of antitumor activity against murine leukemia L1210 of anthrapyrazoles, as well as activated coagulation factor X (FXa) inhibitory activity of isosteviol analogues. These two different sets of molecules [...] Read more.

A multivariate adaptive regression splines (MARSplines) approach was applied to the quantitative structure–activity relationship studies of antitumor activity against murine leukemia L1210 of anthrapyrazoles, as well as activated coagulation factor X (FXa) inhibitory activity of isosteviol analogues. These two different sets of molecules in the first stage underwent molecular modelling studies, i.e., geometrical optimization via the MM+ and the AM1 method using the Polak–Ribiere algorithm, and finally, about 5000 molecular descriptors encoding structural features were calculated. Afterwards, statistical analysis using the MARSplines algorithm was performed, which led to the establishment of a portfolio of submodels. As a result, the statistically significant MARS model that best describes quantitative structure–activity relationships for each set of the studied compounds was chosen. Elaborated models reveal which molecular properties have the greatest impact on the pharmacological activity of anthrapyrazole and isosteviol compounds. Among the independent variables appearing in the statistically significant MARS models, descriptors belonging to 2D Atom Pairs, 2D autocorrelations, 3D-MoRSE, GETAWAY, burden eigenvalues, RDF, and WHIM descriptors may be distinguished. The studies confirmed the benefit of using the MARSplines algorithm, the since high predictive power of the obtained models makes them useful for the prediction of antitumor and FXa inhibitory activity, and this approach can possibly be considered as a tool for searching for new drug candidates. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 199 KiB

Open AccessAbstract

Bioactive Potential of Hibiscus rosa sinensis and Jasminum sambac Extracts against Food Borne Pathogens

by Laiba Rasheed, Rabia Tanvir, Fatima Ahsan and Wasim Shehzad

Med. Sci. Forum 2022, 14(1), 92; https://doi.org/10.3390/ECMC2022-13169 - 1 Nov 2022

Viewed by 761

Abstract

Foodborne diseases (FBD) are a serious issue that affects not only human health but also has an impact on the global economy. They remain a persistent problem due to the continuing changes in global food trade trends, dietary patterns, food manufacturing, and the [...] Read more.

Foodborne diseases (FBD) are a serious issue that affects not only human health but also has an impact on the global economy. They remain a persistent problem due to the continuing changes in global food trade trends, dietary patterns, food manufacturing, and the emergence of foodborne microbes in the food chain. In Pakistan, where meat is considered an essential component of our meals, due to its high nutrient concentration levels, high water activity, minerals and vitamins, and other growth factors such as pH, microbes thrive in it. The extensive use of antibiotics has resulted in antimicrobial resistant (AMR) bacteria in E. coli, Salmonella, Campylobacter, and Listeria spp. Traditional medicinal practices, especially the use of plant extracts, continue to play a crucial role in addressing basic healthcare needs in underdeveloped countries. The purpose of our study was to check the antibacterial potential of Jasminum sambac (jasmine) and Hibiscus rosa sinensis (China rose) extracts against foodborne pathogens, i.e., E. coli, Salmonella, and Campylobacter. The hot and cold extracts were prepared using ethanol and distilled water, and the antibacterial activity was observed by the agar well diffusion method. The minimum inhibitory concentration (MIC) was also carried out on the plant extracts, which gave MIC values of 6 and 12 µg/mL for E. coli and Salmonella, respectively. The minimum bactericidal concentration (MBC) showed that ethanol extracts of both plants possessed bactericidal activity. Our study indicates that the native plants of Pakistan have significant bioactivity against foodborne pathogens. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 181 KiB

Open AccessAbstract

Anti-Inflammatory and Anti-Nociceptive Properties of Leaf Fractions of Sida linifolia L. (Malvaceae) Possibly Mediated by Peripheral and Central Mechanisms

by Nicodemus Emeka Nwankwo, Emmanuel Chimeh Ezeako, Amaechi Lydia Ogara and Emmanuel Henry Ezenabor

Med. Sci. Forum 2022, 14(1), 93; https://doi.org/10.3390/ECMC2022-13488 - 2 Nov 2022

Viewed by 874

Abstract

Sida linifolia L., a common weed found in dry forest areas in West Africa and other parts of the world, is associated with several folkloric applications in Africa, including its use in assuaging painful whitlows and in malaria management; however, limited or no [...] Read more.

Sida linifolia L., a common weed found in dry forest areas in West Africa and other parts of the world, is associated with several folkloric applications in Africa, including its use in assuaging painful whitlows and in malaria management; however, limited or no scientific studies have validated its bioactivities. Herein, we investigated the anti-nociceptive and anti-inflammatory mechanisms of ethanolic (ELFSL) and ethyl acetate (EALFSL) fractions of Sida linifolia leaves. The in vivo anti-inflammatory activities were evaluated by edema induction with an intraperitoneal injection of freshly prepared carrageenan (0.1 mL of 0.01 g/mL) and 0.1 mL of undiluted fresh egg albumin into the mouse’s hind paw; additionally, hind paw licking, and writhing were induced in mice using formalin (i.p.) (0.02 mL of 1% v/v) and 0.6% (v/v) (10 mL/kg bw) (i.p.) acetic acid, respectively, to assay for anti-nociceptive potentials. Varying amounts of flavonoids, tannins, and other phenols, terpenoids, saponins, steroids, and alkaloids were detected in the fractions. The LD₅₀ study showed no toxicity up to 5000 mg/kg body weight (per oral) EALFSL and ELFSL. Interestingly, oral administration of various concentrations (200, 400, and 600 mg/kg bw) of the fractions significantly (p < 0.05) inhibited all phases of edemogenesis, mice’s hind licking, and writhing compared with controls, and were comparable with 100 mg/kg bw (p.o.) aspirin. However, ELFSL showed non-significantly (p > 0.05) better anti-nociceptive and anti-inflammatory activities than EAFSL. This suggests that leaf fractions of Sida linifolia possess anti-inflammatory and anti-nociceptive potentials, possibly mediated by peripheral and central mechanisms. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 202 KiB

Open AccessAbstract

2-Styrylchromones Modulate Prostaglandins Production through the Inhibition of COX-2

by Mariana Lucas, Marisa Freitas, Artur M. S. Silva, Eduarda Fernandes and Daniela Ribeiro

Med. Sci. Forum 2022, 14(1), 94; https://doi.org/10.3390/ECMC2022-13232 - 1 Nov 2022

Viewed by 642

Abstract

2-Styrylchromones (2-SC) are heterocyclic compounds with a structure of at least 17 carbons and a styryl group attached to a benzoannelated γ-pyrone ring. Although the anti-inflammatory potential of 2-SC has become a subject of interest, their effects in inflammatory pathways are still unexplored. [...] Read more.

2-Styrylchromones (2-SC) are heterocyclic compounds with a structure of at least 17 carbons and a styryl group attached to a benzoannelated γ-pyrone ring. Although the anti-inflammatory potential of 2-SC has become a subject of interest, their effects in inflammatory pathways are still unexplored. Therefore, to better understand the mechanisms of anti-inflammatory action of 2-SC, this study investigated the influence of 10 hydroxylated and methoxylated 2-SC on the inhibitory activity of cyclooxygenase (COX-2), through an in vitro non-cellular assay and an ex vivo assay in human whole blood, which were based on the fluorometric detection of prostaglandin (PG) G₂ and colorimetric detection of PGE₂, respectively. A 2-SC hydroxylated at C-7 and C-8 on the A-ring and C-3′ and C-4′ on the B-ring was the most active in the direct inhibition of COX-2 activity, whereas a 2-SC methoxylated at C-4′ on the B-ring was the most active in the ex vivo inhibition of PGE₂ production. The obtained results suggest that the presence of OH groups, especially at C-8 on the A-ring, favor the direct inhibition of COX-2. Conversely, for inhibition of PGE₂ production in a more complex matrix, human blood, it is the presence of an OCH₃ at C-4′ on the B-ring that seems to be important. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 203 KiB

Open AccessAbstract

Development and Evaluation of AT11-Guided Liposomes for Human Papillomavirus Cancer

by Jéssica Lopes-Nunes, Paula A. Oliveira and Carla Cruz

Med. Sci. Forum 2022, 14(1), 95; https://doi.org/10.3390/ECMC2022-13410 - 1 Nov 2022

Viewed by 739

Abstract

Conventional anticancer therapies present low specificity, leading to several secondary effects. To improve these drawbacks, aptamers able to fold into G-quadruplex (G4) are being used to promote drug accumulation in cancer cells. AS1411 is a G4 aptamer able to recognize nucleolin, a protein [...] Read more.

Conventional anticancer therapies present low specificity, leading to several secondary effects. To improve these drawbacks, aptamers able to fold into G-quadruplex (G4) are being used to promote drug accumulation in cancer cells. AS1411 is a G4 aptamer able to recognize nucleolin, a protein overexpressed on cancer cells’ surfaces. This aptamer was tested in clinical trials, but it showed low response rates and suboptimal pharmacokinetics. Nevertheless, AS1411 is being used as a targeting agent. Moreover, AS1411 derivatives were developed, with improved toxicity and high affinity to nucleolin. Thus, we propose to use AT11, an AS1411 derivative, to functionalize liposomes and improve the selectivity of C₈ (a potential anticancer drug) into oral cancer. Therefore, we produced liposomes (blank or C_8-associated) by the ethanol injection method to, then, we functionalized them with AT11-TEG-Cholesteryl. The resulting liposomes were characterized by DLS. C₈ association was determined by UV/vis spectroscopy, and the AT11 functionalization was determined by SDS-PAGE. The effect of blank and C_8-associated liposomes on oral cancer and healthy cells’ viability was determined by MTT, and its internalization of was visualized by confocal microscopy. Liposomes with hydrodynamic diameters of 148–168 nm were obtained, and C₈ was efficiently associated (~100%). When the cells were treated with blank liposomes, cell viability was almost unaffected. After treating with C₈-associated liposomes, both cell lines showed a dose–response effect. Additionally, we observed that AT11-liposomes can internalize and reach the cytoplasm of cells. Overall, these findings suggest that the tested liposomes are promising drug carriers for oral cancer therapy. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 181 KiB

Open AccessAbstract

Ionic Derivatives of Insulin-Mimetic Vanadium(V) Complexes with Schiff Base Ligands

by Anna Jurowska, Janusz Szklarzewicz, Maciej Hodorowicz, Ennio Zangrando and Ghodrat Mahmoudi

Med. Sci. Forum 2022, 14(1), 96; https://doi.org/10.3390/ECMC2022-13167 - 1 Nov 2022

Viewed by 627

Abstract

The biological activity of the vanadium Schiff base complexes, which can be potentially used as insulin-mimetic compounds, was extensively studied in the last decade. Pharmacological data showed that these compounds produced a significant decrease in blood glucose level and improved liver and kidney [...] Read more.

The biological activity of the vanadium Schiff base complexes, which can be potentially used as insulin-mimetic compounds, was extensively studied in the last decade. Pharmacological data showed that these compounds produced a significant decrease in blood glucose level and improved liver and kidney function after two weeks of daily use. The vanadium complexes obtained so far with Schiff bases create problems, most often with cytotoxicity, very low solubility in water, difficulty in studying the crystal structure, instability at pH = 2 and transport to cells. Therefore, it is necessary to search for new organic vanadium compounds to optimize their pharmaceutical activity. Lastly, several hundred vanadium(III–V) complexes with Schiff bases were tested, controlling both the starting vanadium compound for the synthesis of complexes, as well as changing the substituents in the aromatic ring of aldehyde and hydrazide—Schiff base components. The obtained neutral compounds were highly soluble in organic solvents; however, they were insoluble in water. Therefore, the DMSO-H₂O mixture was used to test the stability of the complexes. In the last studies, the synthesis and physicochemical characterization of the vanadium(V) complex with triethylamine as a cation—HTEA[VO₂(L)] (where L = Schiff base formed from 5-bromosalicylaldehyde and 2-hydroxybenzhydrazide)—was described. In the formed ionic complexes, the crystal studies show additional hydrogen interactions between the cation and the complex anion. The ionic structure of such compounds should increase the solubility of the complexes in water, thus maximizing their availability in the biological systems studied. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 188 KiB

Open AccessAbstract

Pd-Catalyzed Cycloaddition of Bicyclic Aziridine with Isocyanates

by Mariana Crespo Monteiro, Carlos A. M. Afonso and Filipa Siopa

Med. Sci. Forum 2022, 14(1), 97; https://doi.org/10.3390/ECMC2022-13424 - 1 Nov 2022

Viewed by 731

Abstract

Nitrogen-containing heterocycles can have several applications in the pharmaceutical industry since they contain a wide spectrum of biological activities. Imidazolidinones have shown activity against leukemia, lung cancer, and metabolic disorders. These cyclic urea frameworks can be obtained through transition-metal-catalyzed intermolecular cycloaddition using an [...] Read more.

Nitrogen-containing heterocycles can have several applications in the pharmaceutical industry since they contain a wide spectrum of biological activities. Imidazolidinones have shown activity against leukemia, lung cancer, and metabolic disorders. These cyclic urea frameworks can be obtained through transition-metal-catalyzed intermolecular cycloaddition using an aziridine moiety as the starting material. These reactions often provide effective one-step procedures that result in heterocyclic derivatives that are challenging to access through conventional approaches. We have previously described the photoreaction of butyl pyridinium salt with the corresponding bicyclic aziridine in continuous flow. Additionally, we reported that the palladium-catalyzed ring opening of bicyclic aziridines with active methylenes exhibited a new S_N2’ selectivity. In this study, the reaction between bicyclic aziridines and several isocyanates, in the presence of Pd(0)-catalyst is presented. The reactions proceed through ring opening of the aziridine moiety, with the formation of the π-allylpalladium complex, followed by cyclization via nucleophilic addition of nitrogen to the isocyanate, affording regioselectively imidazolidinones. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 170 KiB

Open AccessAbstract

YAMACS: A Python Based Tool Kit for GROMACS

by Arkadeep Sarkar, Lucia Sessa, Luigi Di Biasi and Stefano Piotto

Med. Sci. Forum 2022, 14(1), 98; https://doi.org/10.3390/ECMC2022-13433 - 1 Nov 2022

Viewed by 1011

Abstract

Molecular dynamics (MD) is a powerful tool used to study the evolution of molecular systems and predict their properties from the inherent interactions. GROMACS is a famous tool for MD and developed as open-source software. GROMACS is run from the command line with [...] Read more.

Molecular dynamics (MD) is a powerful tool used to study the evolution of molecular systems and predict their properties from the inherent interactions. GROMACS is a famous tool for MD and developed as open-source software. GROMACS is run from the command line with user-provided configuration files. However, the absence of a graphical user interface (GUI) of GROMACS and proper protocol to develop the input files (Ex: itp files, topology files, etc.) prevent the researcher from visualizing the MD trajectory in a real-time manner as well as addressing the structural problem. This issue was addressed by developing a graphical user interface of GROMACS as plugins for the YASARA molecular graphics suite, called YAMACS. YAMACS is an open-source project and is available on GitHub. The tool can perform MD simulations for protein, protein–ligand complexes, membrane–protein complexes, membrane–protein complexes, and small molecule systems. Easily YAMACS automatizes several steps of input file preparation and allows visualizing the MD trajectory in real-time. At this conference, I will present the application of YAMACS to simulate the complex sphingomyelin/POPC embedded in a membrane of POPC. I will also introduce a collaborative platform to create an open community of users and developers, extend the functionalities of YAMACS, and improve the quality of computational drug design studies. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 222 KiB

Open AccessAbstract

Impact of pH on the Antibacterial Activity of Norfloxacin in Its Combined Use with Oxalic Acid against Escherichia coli ATCC 25922

by Rosalía Ayala Gómez, María Cecilia Becerra and Graciela Pinto Vitorino

Med. Sci. Forum 2022, 14(1), 99; https://doi.org/10.3390/ECMC2022-13226 - 1 Nov 2022

Viewed by 773

Abstract

The bacterial susceptibility and the translocation of fluoroquinolones (FQs) are influenced by pH, since it determines the proportion of microspecies of the drug. Norfloxacin (NOR) and oxalic acid (AO) are antibacterial compounds. In this work, we evaluated the antibacterial activity of the NOR–AO [...] Read more.

The bacterial susceptibility and the translocation of fluoroquinolones (FQs) are influenced by pH, since it determines the proportion of microspecies of the drug. Norfloxacin (NOR) and oxalic acid (AO) are antibacterial compounds. In this work, we evaluated the antibacterial activity of the NOR–AO combination on the Escherichia coli American Type Culture Collection 25922 strain using the checkerboard method. In addition, we analyzed the effect of pH on the NOR-AO combination. We determined the extent of NOR ionization equilibrium and calculated the apparent logP to establish the lipophilicity of NOR at the different pHs assayed. The minimum inhibitory concentration (MIC) obtained for AO and NOR was 1250 µg/mL and 0.25 µg/mL, respectively. The interaction of NOR–AO was indifferent to the concentrations tested (Fractional Inhibitory Concentration 1.12). However, an atypical behavior was observed in E. coli growth. We observed that at pH values below 5.8 and log D below −0.3, the cationic species of NOR predominates, decreasing its activity. As pH increased, the predominant species is zwitterionic with increased lipophilicity and restoration of NOR activity. Therefore, the acid conditions given by the presence of AO decreased the concentration of the neutral species of NOR and therefore the amount of drug capable of diffusing directly through the membrane. There is controversy in the literature regarding the mechanism of FQ translocation through the bacterial membrane; however, our results show that the pH of the medium is a determining factor that directly impacts the antibacterial activity. To deepen this study, we will continue testing new concentrations and combinations with other organic acids. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 182 KiB

Open AccessAbstract

Methoxyphenyl Imidazolines as Potential Activators of p53

by Daniil R. Bazanov, Nikolay V. Pervushin, Natalia A. Lozinskaya and Gelina S. Kopeina

Med. Sci. Forum 2022, 14(1), 100; https://doi.org/10.3390/ECMC2022-13494 - 7 Nov 2022

Viewed by 1134

Abstract

The use of p53-MDM2/X inhibitors is a prospective strategy in anti-cancer therapy for tumors with wild type p53 protein. In our study, new low-molecular-weight inhibitors of the p53-mdm2 interaction have been proposed. The two-step synthesis of the imidazoline core with subsequent modifications for [...] Read more.

The use of p53-MDM2/X inhibitors is a prospective strategy in anti-cancer therapy for tumors with wild type p53 protein. In our study, new low-molecular-weight inhibitors of the p53-mdm2 interaction have been proposed. The two-step synthesis of the imidazoline core with subsequent modifications for the nitrogen atom was carried out. New molecules caused the accumulation of p53 protein levels more than seven times than in comparison with the control. The accumulation of proapoptotic proteins such as p21 and PUMA has also been investigated, and the mechanism of cell death has been shown. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 203 KiB

Open AccessAbstract

Ecotoxicological Tools to Assess Cytostatic Effects in Freshwater Environments: Aiding Drug Prioritization

by Cátia Venâncio, Bruna Monteiro, Rafael Francisco, Márcia C. Neves, Mara G. Freire, Ana Catarina A. Sousa and Isabel Lopes

Med. Sci. Forum 2022, 14(1), 101; https://doi.org/10.3390/ECMC2022-13246 - 1 Nov 2022

Viewed by 670

Abstract

Given the growing number of cancer diseases, new cytostatic drugs are approved daily, often with concomitant development, or refinement of some of these drugs aimed at decreasing patient discomfort during the administration period (e.g., prodrugs). Classified as highly toxic, they represent a major [...] Read more.

Given the growing number of cancer diseases, new cytostatic drugs are approved daily, often with concomitant development, or refinement of some of these drugs aimed at decreasing patient discomfort during the administration period (e.g., prodrugs). Classified as highly toxic, they represent a major environmental problem that may potentiate disease occurrences. For newer cytostatic and prodrugs there are no (or few) reported effects to aquatic organisms; therefore, their prioritization is constrained. In light of the points raised, the IonCytDevice project intended to bridge some of these knowledge gaps and has delivered important benchmarks. Predictions have been obtained on the environmental impacts of three cytostatics (cyclophosphamide: CYP; 5-fluoroucil: 5-FU; and mycophenolic acid: MPA) and one prodrug (capecitabine: CAP) on freshwater biota, with a focus on new species and endpoints likely to be also framed in meta-analysis studies. The results reveal that, for now, CYP, 5-FU, and CAP (prodrug) pose no risk, whilst MPA was flagged as a high environmental risk. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 185 KiB

Open AccessAbstract

Silver(I) Complexes with Clinically Used Azoles: Synthesis, Structural Characterization and Antimicrobial Evaluation

by Nevena Lj. Stevanović, Jelena Lazić, Jakob Kljun, Mia Stanković, Jasmina Nikodinovic-Runic, Iztok Turel, Miloš I. Djuran and Biljana Đ. Glišić

Med. Sci. Forum 2022, 14(1), 102; https://doi.org/10.3390/ECMC2022-13249 - 1 Nov 2022

Viewed by 1564

Abstract

Recently, we synthesized silver(I) complex with the antifungal agent itraconazole, which showed improved anti-Candida potential and therapeutic safety in comparison to itraconazole and rescued zebrafish embryos affected by lethal C. albicans infection, when used in safe doses. Inspired by these results, in [...] Read more.

Recently, we synthesized silver(I) complex with the antifungal agent itraconazole, which showed improved anti-Candida potential and therapeutic safety in comparison to itraconazole and rescued zebrafish embryos affected by lethal C. albicans infection, when used in safe doses. Inspired by these results, in the present study, three new silver(I) complexes with clinically used azoles, econazole (ecz), clotrimazole (ctz) and voriconazole (vcz), [Ag(ecz)₂]SbF₆ (Ag1), [Ag(ctz)₂]SbF₆ (Ag2) and {[Ag(vcz)₂]SbF₆}_n (Ag3) were synthesized and structurally characterized by elemental microanalysis, mass spectrometry, spectroscopy (¹H NMR, IR and UV-Vis), cyclic voltammetry, molar conductivity measurements, and single crystal X-ray diffraction analysis. The spectroscopic and crystallographic results revealed that, in the synthesized silver(I) complexes, azole ligands are monodentately coordinated to the Ag(I) ion through the nitrogen atom forming [Ag(azole)₂]⁺ complex cation. The antimicrobial effect of complexes and azole ligands was evaluated against different Candida species, as well as Gram-positive and Gram-negative bacteria. The synthesized complexes Ag1-3 exhibited good to moderate antimicrobial activity being, in most cases, more active than the corresponding azole ligands. Complexes Ag2 and Ag3 also showed strong inhibitory activity against C. albicans biofilm formation and strong inhibition of C. albicans filamentation at subinhibitory concentrations. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 173 KiB

Open AccessAbstract

A Molecular Docking Study on Natural Compounds as Anxiolytics and Antidepressants

by Maria Mernea, Maria-Eliza Satmaru, Alina-Nicoleta Toma, Cristina Doina Niţu, Dan Florin Mihailescu, Speranta Avram and Miruna-Silvia Stan

Med. Sci. Forum 2022, 14(1), 103; https://doi.org/10.3390/ECMC2022-13412 - 1 Nov 2022

Viewed by 1219

Abstract

Anxiety and depression are two conditions that had increased incidences in the context of COVID-19. The administration of current therapies based on anxiolytic and antidepressant drugs can result in adverse reactions and even potential dangers in the case of some patients, such as [...] Read more.

Anxiety and depression are two conditions that had increased incidences in the context of COVID-19. The administration of current therapies based on anxiolytic and antidepressant drugs can result in adverse reactions and even potential dangers in the case of some patients, such as older adults and elderly patients. Aiming to identify safer treatments, we used molecular docking to screen twenty natural compounds against γ-aminobutyric acid A receptor (GABAA receptor), a major drug target in anxiety, and against serotonin transporter (SERT), a major drug target in depression. The list of compounds included molecules that were previously reported as beneficial in the two conditions. In the case of all molecules, we predicted their drug-likeness, bioavailability, and pharmacokinetic profiles. Molecular docking has shown that the top five molecules in terms of affinity for the GABAA receptor are luteolin, baicalein, myricetin, chrysin, and curcumin. In the case of SERT, the top five ligands were myricetin, luteolin, curcumin, apigenin, and fisetin. According to the predictions performed here, these molecules comply with drug-likeness rules, are bioavailable and non-toxic, present a high intestinal absorption, and are distributed to the central nervous system. Our results point toward luteolin, myricetin, and curcumin as common ligands for the GABAA receptor and SERT, suggesting their beneficial effects for both anxiety and depression. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 204 KiB

Open AccessAbstract

Characterization of the Cytotoxic Effect of N-(2-Morpholinoethyl)-2-(naphthalen-2-yloxy)acetamide in Cells Derived from Cervical Cancer

by Cristina Martínez-Nava, Cuauhtémoc Pérez-González, Miguel Ángel Zavala-Sánchez and Carlos Alberto Méndez-Cuesta

Med. Sci. Forum 2022, 14(1), 104; https://doi.org/10.3390/ECMC2022-13304 - 1 Nov 2022

Viewed by 725

Abstract

Cancer is a disease caused by the alteration of proto-oncogenes and tumor suppressor genes, has a high prevalence in the population, and is one of the main causes of death worldwide. For its treatment, there are different therapy options; however, these are not [...] Read more.

Cancer is a disease caused by the alteration of proto-oncogenes and tumor suppressor genes, has a high prevalence in the population, and is one of the main causes of death worldwide. For its treatment, there are different therapy options; however, these are not always effective for all existing types of cancer, which gives rise to the search for new compounds. The objective of this work is to determine the degree of cytotoxic activity of naphthoxyacetamide using dose–response curves in a cell viability assay. For this, the cytotoxic effects of N-(2-morpholinoethyl)-2-(naphthalen-2-yloxy) were identified in cancer cells (HeLa) based on the metabolic reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylretrazol (MTT) bromide. The cell cultures were seeded at a density of 5000 cells/well in 96-well plates and treated by hexapplication with various concentrations of the compounds to be tested (0.31–3.16 µM/mL) for 24 h. Microplates were read in an ELISA reader at 575 nm. The dose–response curve of N-(2-morpholinoethyl)-2-(naphthalen-2-yloxy)acetamide (3.16, 1.77, 1, 0.31 µM/mL) showed that at a concentration of 3.16 µM/mL, it presents cytotoxic effects similar to those shown by the drug reference (cisplatin 3.32 µM/mL). In conclusion, N-(2-morpholinoethyl)-2-(naphthalen-2-yloxy)acetamide showed cytotoxic effects similar to cisplatin. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 221 KiB

Open AccessAbstract

In Vitro Cytotoxicity of 3,3′,4′,7-Tetrahydroxyflavone Derivatives in Human Osteosarcoma

by José Miguel P. Ferreira de Oliveira, Ana T. Rufino, Carina Proença and Eduarda Fernandes

Med. Sci. Forum 2022, 14(1), 105; https://doi.org/10.3390/ECMC2022-13476 - 1 Nov 2022

Viewed by 653

Abstract

Osteosarcoma (OS) is the most common childhood bone sarcoma. Current therapies include preoperative neoadjuvant therapy, tumor resection, and postoperative adjuvant therapy. In cases of recurrent disease, this regimen is limited by poor overall survival rates; therefore, novel therapeutic agents are required. Recently, flavonoids [...] Read more.

Osteosarcoma (OS) is the most common childhood bone sarcoma. Current therapies include preoperative neoadjuvant therapy, tumor resection, and postoperative adjuvant therapy. In cases of recurrent disease, this regimen is limited by poor overall survival rates; therefore, novel therapeutic agents are required. Recently, flavonoids have been reported to inhibit OS development, which suggests the therapeutic benefit of this type of molecules in OS. The aim of this study was to evaluate the cytotoxicity of 3,7,3′,4′-tetrahydroxyflavone compounds in OS. MG-63, Saos-2, HOS, and 143B human OS cell lines were incubated with six flavonoids, at final concentrations of 0–160 µM, for 48 h. After this period, the inhibition of OS cell proliferation and growth was evaluated by WST-8 and sulforhodamine B spectrophotometric assays. The most active inhibitors possessed triple hydroxylation at the B-ring, at C-3′, C-4′, and C-5′. In contrast, hydroxylation at C-5 of the A-ring resulted in poorer inhibition of cell proliferation and growth. These results reveal new substitutions to improve the cytotoxic activity of flavonoids and postulate further investigation of the cellular effects of these compounds in human OS. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 171 KiB

Open AccessAbstract

Design of New Derivatives of Dimedone Molecules Using QSAR and Docking Molecular

by Khaoula Mkhayar, Ossama Daoui, Rachid Haloui, Souad Elkhattabi and Samir Chtita

Med. Sci. Forum 2022, 14(1), 106; https://doi.org/10.3390/ECMC2022-13245 - 1 Nov 2022

Viewed by 795

Abstract

In this work, we investigated the quantitative relationship between biological activity against non-small cell lung cancer (NSCLC) and the molecular structure of a series of 38 cyclohexane-1,3-dione-dimidone derivatives. For this purpose, molecular descriptors calculated by DFT-B3LYP/6-31G, topological, and physicochemical analysis were used. The [...] Read more.

In this work, we investigated the quantitative relationship between biological activity against non-small cell lung cancer (NSCLC) and the molecular structure of a series of 38 cyclohexane-1,3-dione-dimidone derivatives. For this purpose, molecular descriptors calculated by DFT-B3LYP/6-31G, topological, and physicochemical analysis were used. The results of the evaluations of the quantitative activity structure relationship (QSAR) models developed in this work via Multiple Linear Regression and via Multiple Non-Linear Regression (MLR and MNLR) techniques indicate the high predictive power of these models, (R² = 0.913; R²_CV = 0.85, R²_test = 0.934) for the linear model and (R² = 0.991; R²_CV = 0.82; R²_test = 0.997) for the nonlinear model. Using predictions from the QSAR model, new molecular structures were designed, their activity against NSCLC was evaluated, and the most important interactions between these molecules and the human c-Met protein were predicted. The predictions from QSAR models, molecular docking, and an evaluation of the in silico ADMET properties suggested that 1 of the 16 newly designed molecules is a candidate that may be a drug for NSCLC. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Desialylation of Blood Plasma Lipoproteins by Exogenous Sialidase

by Evgeny Bezsonov and Dmitry Kashirskikh

Med. Sci. Forum 2022, 14(1), 107; https://doi.org/10.3390/ECMC2022-13310 - 1 Nov 2022

Viewed by 616

Abstract

Objective: Sialidases can play an important role in atherosclerosis development due to modification of low-density lipoproteins (LDL). It is known that desialylated LDLs are associated with atherosclerosis development. However, the information about factors leading to desialylation of LDL needs clarifying. The creation of [...] Read more.

Objective: Sialidases can play an important role in atherosclerosis development due to modification of low-density lipoproteins (LDL). It is known that desialylated LDLs are associated with atherosclerosis development. However, the information about factors leading to desialylation of LDL needs clarifying. The creation of an appropriate model object could help to understand factors related to desialylation of LDL. The aim of this study was to test the possibility to change sialylation of lipoproteins in healthy mice upon an injection of immobilized sialidase. Methods: The control group of C57BL6 mice (n = 48) was treated by a single injection of saline, while the experimental group (n = 48) received Vibrio cholerae sialidase conjugated with mouse IgG. Mice were terminated at fixed periods: before and after a single injection (one to seven days). LDL was isolated from serum by ultracentrifugation. The content of sialic acid was determined according to Warren’s method. Lipids of serum were measured by commercial kits. Results: A significant decrease in LDL sialic acid by 30% was detected up to five days after the sialidase injection. Additionally, serum levels of triglycerides, total cholesterol, and HDL-cholesterol in experimental mice did not differ compared with wild-type control mice. Conclusions: A new approach to study the role of sialidase as a proatherogenic factor in vivo was established. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 200 KiB

Open AccessAbstract

Synthesis and Chemical Reactivity of Novel Polyhydroxylated Bis-Chalcones

by Rui Pereira, Vera L. M. Silva, Artur M. S. Silva, Daniela Ribeiro and Eduarda Fernandes

Med. Sci. Forum 2022, 14(1), 108; https://doi.org/10.3390/ECMC2022-13473 - 1 Nov 2022

Viewed by 667

Abstract

Chalcones, a class of compounds characterized by two aromatic rings linked through a three carbon α,β-unsaturated carbonyl system, aroused widespread interest due to their (bio)synthesis and broad biological activities. However, less attention has been given to a subcategory of chalcones, bis-chalcones, despite [...] Read more.

Chalcones, a class of compounds characterized by two aromatic rings linked through a three carbon α,β-unsaturated carbonyl system, aroused widespread interest due to their (bio)synthesis and broad biological activities. However, less attention has been given to a subcategory of chalcones, bis-chalcones, despite some studies suggesting that they have improved bioactivities in comparison to their mono derivatives. Their synthesis is relatively less explored and typically requires longer reaction times and harder purifications, especially for derivatives with free hydroxy groups. This issue is relevant because several activities of bis-chalcones have been associated with the presence of hydroxy groups in the structure. In this context, the objectives of this work were to establish an efficient methodology for the synthesis of novel polyhydroxylated bis-chalcones and bis-chalcones containing other substituent groups such as halogen, methoxy, and prenyl groups and explore their chemical reactivity for further transformation into other potentially bioactive flavonoids. Herein, we report our most recent results on the synthesis of bis-chalcones and their transformation into bis-flavones. Bis-chalcones were obtained in good yields (50–80%) by basic catalyzed Claisen–Schmidt condensation of methoxymethyl (MOM)/Me-protected bis-acetophenones with aromatic aldehydes, followed by deprotection of MOM groups in an acidic medium. In turn, a prenylated bis-chalcone was prepared by O-prenylation of the hydroxylated bis-acetophenone followed by Claisen rearrangement and Claisen–Schmidt condensation with 4-methoxymethylbenzaldehyde. Afterwards, some unprotected bis-chalcones were successfully cyclized into bis-flavones through cyclodehydrogenation with I₂/ dimethyl sulfoxide (DMSO). In the future we intend to evaluate the anti-inflammatory activity of these compounds. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 215 KiB

Open AccessAbstract

Potential of Antioxidant-Loaded Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for the Management of Neurodegenerative Diseases

by Joana Torres, José Miguel Pereira, Renata Silva, Rita Marques Oliveira, Andreia Filipa Peixoto, José Manuel Sousa Lobo and Ana Catarina Silva

Med. Sci. Forum 2022, 14(1), 109; https://doi.org/10.3390/ECMC2022-13417 - 1 Nov 2022

Cited by 1 | Viewed by 729

Abstract

The intranasal route has been suggested as a promising alternative to improve drug delivery to the central nervous system, as it can transport drugs from the nose directly to the brain, avoiding the need to cross the blood-brain barrier and, therefore, can represent [...] Read more.

The intranasal route has been suggested as a promising alternative to improve drug delivery to the central nervous system, as it can transport drugs from the nose directly to the brain, avoiding the need to cross the blood-brain barrier and, therefore, can represent an effective strategy in the treatment of neurodegenerative diseases. Natural compounds, existent in marine microorganisms, can be used in the management of neurodegenerative diseases due to their remarkable antioxidant activity that reduces the oxidative stress associated with the development of these diseases. The objective of this work was to prepare solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for nose-to-brain delivery loaded with 1000 µg/mL of two natural antioxidants, in particular antioxidant extract and pure antioxidant. On the day of the production, all formulations had a particle size, polydispersity index and zeta potential suitable for nose-to-brain administration. In addition, all formulations showed high encapsulation efficiency of the tested natural antioxidants. Six months after storage at 20.0 ± 0.5 °C, in the case of SLN and NLC with antioxidant extract, and one month after storage, in the case of SLN and NLC with pure antioxidant, the characterization parameters underwent only slight changes. Biocompatibility studies in human neuronal cells SH-SY5Y, showed that the developed formulations are safe at least at concentrations up to 100 µg/mL. The results of this study highlighted the potential of using lipid nanoparticles loaded with natural antioxidants in the management of neurodegenerative diseases, although more experiments are needed to confirm this evidence. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 213 KiB

Open AccessAbstract

Development of a Cowpea Immature Pod Purée: An Opportunity for the Elderly to Improve Their Autonomy in Daily Living Activities and Quality of Life

by Catarina Passão, Alfredo Aires, Miguel Rodrigues, Luís Ferreira, Irene Gouvinhas and Ana Barros

Med. Sci. Forum 2022, 14(1), 110; https://doi.org/10.3390/ECMC2022-13229 - 1 Nov 2022

Viewed by 788

Abstract

The nutritional composition of cowpea (Vigna unguiculata (L.) Walp.) has been related to the prevention of diverse metabolic and cardiovascular diseases. Previous works have shown that cowpea immature pods exhibited higher phenolic composition and antioxidant activity as compared to immature and dry [...] Read more.

The nutritional composition of cowpea (Vigna unguiculata (L.) Walp.) has been related to the prevention of diverse metabolic and cardiovascular diseases. Previous works have shown that cowpea immature pods exhibited higher phenolic composition and antioxidant activity as compared to immature and dry seeds. This work aims to develop a cowpea immature pod ready-to-eat purée for the elderly to promote the maintenance of their muscle mass and synthesis of neurotransmitters implicated in depression disorder and sleep quality. In a preliminary approach, this study intends to assess the phenolic content, antioxidant capacity, nutritional composition, and essential and non-essential amino acids of the cowpea at two different growth stages: immature pods and green seeds. Immature pods showed a significantly higher content of total phenols (11.73 ± 0.43 mg AG/g dry weight), ortho-diphenols (13.18 ± 1.26 mg GA/g dw), and flavonoids (6.04 ± 0.51 mg CAT/g dw) as compared to the green seeds. The higher antioxidant capacity was also displayed by the pods (ABTS•⁺ (2-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical): 0.05 ± 0.00 mmol Trolox/g dw, DPPH• (2,2-diphenyl-1-picrylhidrazyl radical): 0.04 ± 0.00 mmol Trolox/g dw, FRAP (Ferric Reduction Antioxidant Power): 0.04 ± 0.00 mol Trolox/g dw) in contrast with the green seeds. Immature pods demonstrated the lowest crude fat content (1.74 ± 0.03%) and the highest content of crude protein (27.48 ± 1.05%) and of insoluble dietary fibre (35.63 ± 0.53%). To our knowledge, we present the first study concerning the nutritional composition of cowpea immature pod, suggesting that it has remarkable potential to be included in the development of a new functional food product for the elderly. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 188 KiB

Open AccessAbstract

Computational Design of New Teixobactin Analogues as Inhibitors of Lipid II Flippase MurJ

by Andreea Calianu and Radu Tamaian

Med. Sci. Forum 2022, 14(1), 111; https://doi.org/10.3390/ECMC2022-13295 - 1 Nov 2022

Viewed by 809

Abstract

The peptidoglycan (PG) cell wall is an essential component of the bacterial cell structure, and crippling its synthesis is one of the most successful strategies in the continuing war against pathogenic bacteria. MurJ is a member of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily which [...] Read more.

The peptidoglycan (PG) cell wall is an essential component of the bacterial cell structure, and crippling its synthesis is one of the most successful strategies in the continuing war against pathogenic bacteria. MurJ is a member of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily which is critically required for the synthesis of PG from lipid II. Teixobactin (TXB) is a recently discovered, promising macrocyclic depsipeptide natural antibiotic. TXB is claimed to “kill pathogens without detectable resistance” and is considered a possible “paving stone toward a new class of antibiotics”. In the context of the current antibiotic resistance crisis, the rapid development of a plethora of TXB analogs with improved pharmacokinetics/pharmacodynamics (PK/PD) is a critical challenge. This study focuses on the computational design of new TXB analog prototypes—disruptors of PG cell wall biosynthesis by the inhibition of MurJ. A combinatorial library was generated in silico using a set of three scaffolds based on the TXB structure and a selected list of building blocks in order to avoid the molecular obesity issue and minimize the potential toxicity concerns and health risks. TXB and the combinatorial library were virtually screened with adequate drug-likeness filters and PK/PD models. The safest drug candidates were docked with PyRx v.0.9.7 against the crystal structure of MurJ. What was found was that 26 virtual analogs had better binding affinities than TXB against MurJ. Overall, the proposed computational drug design approach for novel antibiotics might be a useful asset for medicinal chemists and translational pharmacologists. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 172 KiB

Open AccessAbstract

The Use of Fluorescent Optical Respirometry to Study the Antimicrobial Activity of Plant Products and Evaluation of the Pharmaceutical Preparations

by Rafał Hałasa, Katarzyna Turecka and Czesława Orlewska

Med. Sci. Forum 2022, 14(1), 112; https://doi.org/10.3390/ECMC2022-13256 - 1 Nov 2022

Viewed by 738

Abstract

The determination of the number of microorganisms is crucial in the biotechnology, pharmacy, and food industries. Monitoring the quality of pharmaceuticals and food products requires rapid, sensitive, and selective methods to detect minute numbers of viable bacterial cells. Isolation of the natural compounds [...] Read more.

The determination of the number of microorganisms is crucial in the biotechnology, pharmacy, and food industries. Monitoring the quality of pharmaceuticals and food products requires rapid, sensitive, and selective methods to detect minute numbers of viable bacterial cells. Isolation of the natural compounds presented in foods with antibacterial properties requires the testing of many samples and detection of many bacteria in a short period of time. Counting bacteria on the agar plates, membrane filters, and using the “most probable number" are basic methods used to determine the number of live bacteria. These methods require a long incubation time, colonies may be formed by several related species of bacteria, and full identification takes up to seven days. The serial dilution method in broth is used in clinical microbiology and allows for the determination of the minimum inhibitory concentration. However, the length of the assay time and the impact of the physical properties of the sample affect the results. We used the fluorescence oxygen-sensitive sensor ruthenium-tris(4,7-diphenyl-1,10-phenanthroline) dichloride (Ru(DPP)₃Cl₂), the fluorescence of which depends on the amount of oxygen in the tested sample. This sensor was applied in the fluorescent optical respirometry (FOR) method. Molecular oxygen is a fluorescence quencher. Growing microorganisms consume oxygen, thus affecting fluorescence intensity in the sample. The FOR method was performed to evaluate the effect of chemical and environmental factors and plant extracts on aerobic bacteria. The FOR method allows the detection of bacteria in sterile and non-sterile pharmaceutical products. This method allows also for a rapid, unequivocal detection and counting of live bacterial cells. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 187 KiB

Open AccessAbstract

Synthesis, Structural Characterization, and In Silico ADMET Testing of Novel 17β-Acetoxy-17α-(Pyridin-2-yl) Estrane Derivatives

by Milica Stevanović and Ivana Kuzminac

Med. Sci. Forum 2022, 14(1), 113; https://doi.org/10.3390/ECMC2022-13235 - 1 Nov 2022

Cited by 1 | Viewed by 629

Abstract

Steroidal compounds that contain a heterocyclic ring or heteroatom in their structure usually possess good anticancer activity. The main goal of modern medicinal chemistry is to find new potent agonists or antagonists of naturally occurring hormones for the treatment of hormone-dependent cancers, such [...] Read more.

Steroidal compounds that contain a heterocyclic ring or heteroatom in their structure usually possess good anticancer activity. The main goal of modern medicinal chemistry is to find new potent agonists or antagonists of naturally occurring hormones for the treatment of hormone-dependent cancers, such as the above-mentioned steroid derivatives. Here, we reported on a two-step synthesis of a new 17β-acetoxy-17α-(pyridin-2-yl) derivative of estra-1,3,5(10)-triene. The configuration at the C17 position was determined using the 2D NMR spectra. Furthermore, in silico ADME properties were determined for the synthesized compound. The physicochemical properties were calculated with the SwissADME web tool and compared with five different sets of criteria: Lipinski, Veber, Egan, Ghose, and Muegge. The toxicity of the synthesized compound was predicted and analyzed using a virtual lab ProTox II. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 200 KiB

Open AccessAbstract

Bimodal Nanoprobes Containing Hydrophilic Quantum Dots and Paramagnetic Chelates

by Rebeca Muniz de Melo, Gabriela Marques Albuquerque, Giovannia Araújo de Lima Pereira and Maria Goreti Carvalho Pereira

Med. Sci. Forum 2022, 14(1), 114; https://doi.org/10.3390/ECMC2022-13307 - 1 Nov 2022

Viewed by 827

Abstract

Currently, there is a growing interest in the development of bimodal systems that have a signal for more than one diagnostic imaging technique, such as magnetic resonance imaging (MRI). MRI is able to distinguish pathological from healthy tissues; however, in some cases, a [...] Read more.

Currently, there is a growing interest in the development of bimodal systems that have a signal for more than one diagnostic imaging technique, such as magnetic resonance imaging (MRI). MRI is able to distinguish pathological from healthy tissues; however, in some cases, a high local concentration of contrast agents (CAs) is necessary to improve the contrast in images. Nanoparticulate CAs are able to concentrate several CA molecules into one nanoparticle, increasing the local concentrations of paramagnetic ions. In this work, we intend to associate AgInSe₂ quantum dots (QDs) with gadolinium complexes (DOTA-Gd) to develop bimodal systems. The QDs were prepared in water and the synthesis parameters were optimized. The ligand DOTA was conjugated with cysteamine and complexed with Gd³⁺. The complex was then conjugated to QDs through the metal–thiol bond, obtaining the bimodal systems. Optical characterization indicated that the QDs remained stable and fluorescent, and an increase in emission intensity after conjugation was observed. The systems were characterized by relaxometry at 20 MHz (0.47 T) and 37 °C, obtaining longitudinal relaxivities by Gd³⁺ higher than the CAs used clinically. Thus, the prepared nanoprobes showed promising properties for MRI and optical imaging. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 197 KiB

Open AccessAbstract

Podophyllotoxin Content Analysis of Linum album Kotschy ex Boiss. Subjected to Short-Term Potassium Deficiency Stress

by Zahra Danaeipour, Ghasemali Garoosi, Masoud Tohidfar, Mohammad Reza Bakhtiarizadeh and Mohammad Hossein Mirjalili

Med. Sci. Forum 2022, 14(1), 115; https://doi.org/10.3390/ECMC2022-13420 - 1 Nov 2022

Viewed by 722

Abstract

Podophyllotoxin (PTOX), one of the most important natural medicinal compounds, has anticancer properties. Its effective medicinal derivatives, such as etoposide and teniposide, have been approved by the Food and Drug Administration (FDA) for cancer treatment. This compound is found as a specialized metabolite [...] Read more.

Podophyllotoxin (PTOX), one of the most important natural medicinal compounds, has anticancer properties. Its effective medicinal derivatives, such as etoposide and teniposide, have been approved by the Food and Drug Administration (FDA) for cancer treatment. This compound is found as a specialized metabolite in the Linum album Kotschy ex Boiss., belonging to the Linaceae family. PTOX is the major aryltetralin lignan resulting from the shikimic acid/phenylpropanoid pathway, and it accumulates in the shoots and roots of L. album. PTOX plays a necessary role in plant defense systems, protecting against abiotic as well as biotic stresses and helping their adaptation to adverse environmental conditions. Therefore, the content of specialized metabolites increases under stress. In this study, the content of PTOX under stressful conditions (potassium deficiency stress at two time points: 12 and 48 h) was examined using High Performance Liquid Chromatography (HPLC) in a completely randomized design with three replications. The results of HPLC showed that the content of PTOX first decreased after 12 h, while after 48 h of treatment, compared with the control plants, it showed a significant increase, with a value of 135.8 in the shoots. In the roots, the results were consistent with the results of the aerial parts, and the amount increased significantly after 48 h. In general, the results show that L. album, as a suitable natural source for PTOX, has great potential to generate large-scale products for commercial and pharmaceutical purposes. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 210 KiB

Open AccessAbstract

Chalcones as Potential Inhibitors of Pancreatic Lipase

by Sílvia Rocha, Álvaro Tomé, Ana Teresa Rufino, Marisa Freitas, Félix Carvalho, Artur Silva and Eduarda Fernandes

Med. Sci. Forum 2022, 14(1), 116; https://doi.org/10.3390/ECMC2022-13413 - 1 Nov 2022

Viewed by 843

Abstract

Obesity is a global disease that has been escalating to epidemic proportions over the past years. A recent report from World Obesity Federation predicts that, in 2030, 1 billion people will be obese. Thus, it is mandatory to develop new therapeutic options that [...] Read more.

Obesity is a global disease that has been escalating to epidemic proportions over the past years. A recent report from World Obesity Federation predicts that, in 2030, 1 billion people will be obese. Thus, it is mandatory to develop new therapeutic options that can manage and control obesity. One of the most promising research paths is the inhibition of pancreatic lipase (PL), responsible for the hydrolysis of 50 to 70% of total dietary triglycerides. Chalcones are the precursors of flavonoids, consisting of two benzene rings connected by a three-carbon α, β-unsaturated carbonyl structure. The goal of the present work was to evaluate the activity of seven chalcones with hydroxy (OH) and chloride (Cl) substituents, as potential inhibitors of PL. For this purpose, spectrophotometric and fluorometric microanalysis systems were used, based on the enzymatic metabolization of p-nitrophenyl butyrate and 4-methylumbeliferyl oleate, respectively. The obtained results showed that chalcones inhibit PL activity, and that the fluorometric method can reach higher inhibition rates with fewer compounds than the spectrophotometric method. These findings bring new insights into the structure design for the modulation of PL, but further studies are still needed to further explore these compounds as potential anti-obesity molecules. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 215 KiB

Open AccessAbstract

Design, Synthesis and Biological Evaluation of Novel 1H-benzo[d]imidazole Derivatives as Fatty Acid Synthase (FASN) Inhibitors for Cancer Treatment

by Shailendra Singh, Subarno Paul, Chandrabose Karthikeyan, Natércia F. Brás, Chanakya Nath Kundu and Narayana Subbiah Hari Narayana Moorthy

Med. Sci. Forum 2022, 14(1), 117; https://doi.org/10.3390/ECMC2022-13414 - 1 Nov 2022

Viewed by 726

Abstract

FASN is a metabolic oncoprotein that is overexpressed in multiple cancers and regulates the fatty acid requirements of proliferating cells. Thus, FASN has been proposed as a promising target for anticancer drug discovery. Herein, we report the de novo design and synthesis of [...] Read more.

FASN is a metabolic oncoprotein that is overexpressed in multiple cancers and regulates the fatty acid requirements of proliferating cells. Thus, FASN has been proposed as a promising target for anticancer drug discovery. Herein, we report the de novo design and synthesis of small-molecule FASN inhibitors (CTL) that targets breast and colorectal cancer. Our structure–activity relationship studies led to the identification of CTL-1 and CTL-7 as potent, selective FASN inhibitors with IC₅₀ values of 2.5 and 3.0 µM respectively. CTL-1 and CTL-7 inhibited the proliferation of colon cancer cells (HCT-116 and CaCO2) in and of breast cancer cells ( MCF-7 and MDA-MB-231) at less than 10 µM concentration. However, in the non-cancerous cell line HEK-293, the IC₅₀ of CTL-1 and CTL-7 was above 30 µM. Further, cell cycle analysis and apoptosis induction studies of CTL-1 and CTL-7 in HCT-116 cells revealed S-phase arrest along with a prolonged apoptotic effect. Western blot analysis of CTL-1 and CTL-7 established FASN pathway participation in causing cancer cell apoptosis. Molecular dynamics simulation studies of the compounds in KR-domain of the target indicate that CTL-1 and CTL-7 have a high affinity of for the FASN enzyme. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 199 KiB

Open AccessAbstract

The Value of Food Waste: Citrus reticulata (Mandarin) Peel as a Potent Biological Agent

by Mariana Oalđe Pavlović, Ana Alimpić Aradski, Petar D. Marin and Sonja Duletić-Laušević

Med. Sci. Forum 2022, 14(1), 118; https://doi.org/10.3390/ECMC2022-12916 - 26 Sep 2022

Viewed by 573

Abstract

Citrus reticulata (mandarin) is used in the food industry mainly for juice production, while its peel represents a byproduct with a high content of miscellaneous biologically active compounds. This research aimed to assess the antioxidant and enzyme-inhibitory activities of different peel extracts of [...] Read more.

Citrus reticulata (mandarin) is used in the food industry mainly for juice production, while its peel represents a byproduct with a high content of miscellaneous biologically active compounds. This research aimed to assess the antioxidant and enzyme-inhibitory activities of different peel extracts of mandarin cultivated under natural conditions in the Montenegrin coastal region (Lastva Grbaljska). Mandarin fruits were collected in November 2017, and their extracts were prepared using acetone, methanol, and boiling distilled water as solvents. Total phenolic (TPC) and flavonoid (TFC) contents were determined at the concentration of 0.5 mg/mL, as well as the extracts’ antioxidant (using DPPH and total reducing power assays) and enzyme-inhibitory activities (using acetylcholinesterase (AChE) and α-glucosidase inhibition assays). The results indicated that the acetonic extract exhibited the highest radical scavenging activity (12.70%) while also showing the highest TPC (52.40 mg GAE/g) and TFC (13.05 mg QE/g), which is not surprising since acetone is known to extract highly biologically active flavonoid aglycones from plants. Although the aqueous extract had the lowest TPC and TFC, it exerted the highest reducing power (199.06 µmol AAE/g), as well as AChE inhibition activity (22.44%), indicating that other groups of phytochemicals besides phenolics, such as various classes of glycosides, are responsible for the displayed bioactivity. Moreover, none of the extracts inhibited the activity of α-glucosidase. Finally, this study suggests that mandarin peel should not be dismissed in food processing since it possesses a valuable medicinal potential that has yet to be further investigated. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 200 KiB

Open AccessAbstract

Miconazole Nanoemulsions to Treat Melanoma: A Study of Formulation Development, Droplet Size and Solubility

by Joana Amado, Patrícia C. Pires, Francisco Veiga and Ana Cláudia Santos

Med. Sci. Forum 2022, 14(1), 119; https://doi.org/10.3390/ECMC2022-13416 - 1 Nov 2022

Cited by 1 | Viewed by 866

Abstract

Melanoma is one of the most dangerous skin cancers, with a high mortality rate and an incidence that has increased radically in the past few years. This has led to a huge demand for new more effective forms of treatment. Nanoemulsions have been [...] Read more.

Melanoma is one of the most dangerous skin cancers, with a high mortality rate and an incidence that has increased radically in the past few years. This has led to a huge demand for new more effective forms of treatment. Nanoemulsions have been investigated as potential drug delivery vehicles to target cancer cells, since they are a promising alternative to increase the solubility and the skin permeation and retention of hydrophobic drugs. The purpose of this work was to incorporate miconazole, a hydrophobic antifungal drug with potential anticancer activity, into an oil-in-water (O/W) nanoemulsion for topical administration for the treatment of melanoma. Seventeen O/W nanoemulsions were prepared via spontaneous emulsification. The preconcentrate was composed of Plurol® Diisostearique, Transcutol® HP and Kolliphor® RH 40, while the aqueous phase was water. A visual examination was performed to confirm the absence of phase separation and heterogeneity. Analysis using dynamic light scattering (Zetasizer Nano ZS apparatus, Malvern, UK) followed to determine the droplet size and polydispersity index (PDI). Nanoemulsions with a PDI below 0.300 and a droplet size between 100 and 200 nm were selected for solubility assays. After drug incorporation, at 5 mg/mL, only one out of the seventeen nanoemulsions showed characteristics within the intended parameters. In conclusion, this study showed that the incorporation of miconazole in nanoemulsions allows us to greatly increase its solubility when compared to water (up to 6550 times). Future studies will include the determination of viscosity, stability, in vitro drug release, ex vivo drug permeation and in vitro cytotoxicity in melanoma cells. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 195 KiB

Open AccessAbstract

Anthrarufin and Its Anionic Moieties as Potential Inhibitors of HIV-1 Reverse Transcriptase (RT)

by Svetlana Jeremić, Ana Kesić, Jelena Đorović Jovanović and Zoran Marković

Med. Sci. Forum 2022, 14(1), 120; https://doi.org/10.3390/ECMC2022-13502 - 8 Nov 2022

Viewed by 1213

Abstract

At the end of the last century, it was revealed that quinones with one, two, and three aromatic rings could inhibit HIV-1 protease, an enzyme crucial for HIV (Human Immunodeficiency Virus) replication. Since HIV-1 protease acts as key target for AIDS (Acquired Immunodeficiency [...] Read more.

At the end of the last century, it was revealed that quinones with one, two, and three aromatic rings could inhibit HIV-1 protease, an enzyme crucial for HIV (Human Immunodeficiency Virus) replication. Since HIV-1 protease acts as key target for AIDS (Acquired Immunodeficiency Syndrome) medications, the development of efficient inhibitor of this protein would lead to an increase in medical treatment and a decrease in the drug resistance. Later research revealed that hydroxyquinones can block HIV-1 protease at the micromolar level, which enabled a direction for the creation of HIV medications. Anthrarufin (1,5-dihydroxy-9,10-anthraquinone) is an anthraquinone that possesses a moderate antioxidative capacity and antimalaric activity. In this study, molecular docking simulations were used to examine the molecular interactions between anthrarufin, its monoanion and dianion as ligands, and HIV-1 reverse transcriptase (HIV-1 RT) as a target protein. Using AGFR software, the binding site of the HIV-1 RT was identified. The three-dimensional crystal structure of HIV-1 RT was downloaded from the Protein Data Bank (PDB ID: 2ZD1). Dolutegravir, nevirapine, anthrarufin, anthrarufin-anion and anthrarufin-dianion are used as ligands in the molecular docking simulations together with rilpivirine (TMC278), a non-nucleoside inhibitor of estimated protein. The AutoDock 4.0 program is used for molecular docking simulations. Anthrarufin, its monoanion and dianion can be considered as a potential HIV-1 RT inhibitors because they have similar inhibitory potency to other ligands under consideration, according to the results of the free energy of binding (∆G_bind) and inhibition constant (K_i) values. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 186 KiB

Open AccessAbstract

In Silico Investigations of Dihydrophenanthrene Derivatives as Potential Inhibitors of SARS-CoV-2

by Imane Yamari, Suraj N. Mali, Ossama Abchir, Hassan Nour, Said Gmouh, M’Hammed El Kouali and Samir Chtita

Med. Sci. Forum 2022, 14(1), 121; https://doi.org/10.3390/ECMC2022-13293 - 1 Nov 2022

Viewed by 689

Abstract

Since its appearance in Wuhan in December 2019, finding ways to manage the COVID-19 pandemic has become the biggest challenge the world is facing. In this investigation, we used a quantitative structure-activity relationship (QSAR) study, an absorption, distribution, metabolism, excretion, and toxicity (ADMET) [...] Read more.

Since its appearance in Wuhan in December 2019, finding ways to manage the COVID-19 pandemic has become the biggest challenge the world is facing. In this investigation, we used a quantitative structure-activity relationship (QSAR) study, an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and computational molecular docking simulations to screen and assess the efficacy of 39 bioactive 9,10-dihydrophenanthrene analogues. The density functional theory (DFT) using the B3LYP/6-31G (d, p) level was used for the calculations of molecular descriptors, and principal component analysis (PCA) was used to eliminated redundant and non-significant descriptors. After that, statistically robust models were developed using the multiple linear regression (MLR) method. All the derived models were then subjected to thorough external and internal statistical validations, Y-randomization, and applicability domain analysis. These validations were carried out as per the Organisation for Economic Co-operation and Development (OECD) principles. The best built model was used to design new molecules that have good values of inhibitory activity against SARS-CoV-2. The pharmacokinetics properties were then determined using an ADMET analysis to weed out any that would be harmful to the human body or cause adverse effects. Through the use of computational molecular docking simulations, in silico research was conducted on the deigned compounds to forecast their SARS-CoV-2 activity and determine the stability of the evaluated ligands during their contacts with the proteins of the desired activity. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Broad-Spectrum Activity of Antimicrobial Peptoids

by Gill Diamond, Erika Figgins, Denny Gao, Annelise E. Barron and Kent Kirshenbaum

Med. Sci. Forum 2022, 14(1), 122; https://doi.org/10.3390/ECMC2022-13491 - 4 Nov 2022

Viewed by 1191

Abstract

Antimicrobial peptides (AMPs) are naturally occurring host defense molecules, representing an evolutionarily ancient, innate immune mechanism against pathogenic infection. As such, many of these predominantly cationic and amphipathic peptides have been examined for their potential as anti-infective agents. AMP families such as the [...] Read more.

Antimicrobial peptides (AMPs) are naturally occurring host defense molecules, representing an evolutionarily ancient, innate immune mechanism against pathogenic infection. As such, many of these predominantly cationic and amphipathic peptides have been examined for their potential as anti-infective agents. AMP families such as the defensins and cathelicidins exhibit broad-spectrum antimicrobial activity against a wide variety of bacteria, fungi and viruses, initially and predominantly by disruption of the microbial membrane. Due to this physical mechanism, development of resistance by the pathogen is rare. Thus, they represent a great potential for a new type of anti-infective agent. However, due to a variety of reasons, including protease sensitivity and poor bioavailability, they have not been developed into actual therapeutics. To circumvent these issues, we have examined the potential for small molecule mimetics of AMPs, which would be protease-resistant and have better bioavailability. We previously demonstrated the activity of one such class of mimetics, sequence-specific N-substituted glycine oligomers, or peptoids, against the human viral pathogen Herpes Simplex Virus-1 (HSV-1), as well as some bacteria. Here, we compare the activity, both in vitro and in vivo, of select peptoids against bacteria, fungi and viruses, to begin to study the structure/activity relationship with a broad spectrum of microbial pathogens. Our results show that some peptoid structures are more active against one type of pathogen than another. However, at least two of the tested peptoids exhibit potent activity against Gram positive bacteria, Gram negative bacteria, fungi and viruses. Our results suggest that these molecules can be developed into potent broad-spectrum antimicrobial agents. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 169 KiB

Open AccessAbstract

Determination and Evaluation of Acteoside Content of Scrophularia striata Boiss. under Lead Stress

by Reyhaneh Danaeipour and Mohsen Sharifi

Med. Sci. Forum 2022, 14(1), 123; https://doi.org/10.3390/ECMC2022-13305 - 1 Nov 2022

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Abstract

Scrophularia striata Boiss. (Scrophulariaceae family), as an important medicinal plant, is one of the species native to Western Iran. This perennial herbaceous plant has been traditionally used to cure various diseases, including eye and ear infections, inflammation, infectious wounds, colds, and boils, and [...] Read more.

Scrophularia striata Boiss. (Scrophulariaceae family), as an important medicinal plant, is one of the species native to Western Iran. This perennial herbaceous plant has been traditionally used to cure various diseases, including eye and ear infections, inflammation, infectious wounds, colds, and boils, and is also used to treat bacterial, fungal, and viral infections in the world. Since the COVID-19 pandemic outbreak, Ongoing efforts are proceeding worldwide to develop an efficient vaccine and use approaches to find preventive measures and effective treatment. S. striata was introduced as a phenylethanoid glycosides (PhGs) source. S. striata functions as a resistant plant under various stresses. The essential mechanism in response to abiotic and biotic stress is the production of phenolic compound precursors, which eventually leads to PhG compound accumulation, especially acteoside, in this plant. Acteoside operates as a powerful antioxidant that scavenges excess ROS content in biological systems. The study purposed to evaluate the acteoside content in response to Pb stress of S. striata. HPLC analysis was employed to identify PhGs between the untreated and Pb-treated shoots plants with three gathering times (24, 48, and 72 h). Our results indicated that acteoside increased significantly after 72 h under Pb stress, and no significant difference was observed in other time courses. In general, S. striata is a good source of PhGs, especially acteoside, with application in the pharmaceutical industry. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 223 KiB

Open AccessAbstract

Molecular Docking Studies of Antimalarial Compounds from the Acetonic Extract of Cecropia obtusifolia

by Yolotl Moreno-Hernández, Carlos Alberto Lobato-Tapia and Zendy Evelyn Olivo-Vidal

Med. Sci. Forum 2022, 14(1), 124; https://doi.org/10.3390/ECMC2022-13465 - 1 Nov 2022

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Abstract

Malaria is a disease that affects many people in the world. In Mexico, malaria is still a disease with active zones, especially in the states of Chiapas and southern Chihuahua where several communities are affected year after year. According to previous studies, a [...] Read more.

Malaria is a disease that affects many people in the world. In Mexico, malaria is still a disease with active zones, especially in the states of Chiapas and southern Chihuahua where several communities are affected year after year. According to previous studies, a moderate antimalarial effect has been attributed to some Cecropia species in several countries, such as Brazil, Panama, and Colombia. To date in Mexico, no studies have evaluated the possible antimalarial activity of Cecropia Obtisifolia Bertol. The objective of the present study was to identify the main metabolites present in the acetonic extract of C. Obtusifolia and to evaluate their possible antimalarial activity in silico analysis. An acetonic extraction of C. Obtusifolia leaves was performed using Thin-Layer Chromatography (TLC) and high performance liquid chromatography HPLC, and the main compounds were identified. The identified compounds were evaluated with specific molecular docking studies using four different malarial targets with the PDB codes 1CET, 1PZ4, 2BL9, and 4ZL4; the evaluation was performed using AutodockVina and visualized using LigPlot and PyMOL. From the acetone extract, the compounds were found to be ursolic acid, α-amyrin, chrysin, and isoorientin using TLC and HPLC. The docking studies showed that the ligands docked well with the targets, resulting in the following strongest binding energies between the ligands and the targets (kcal/mol): isoorientin–1CET (−9.1), chrysin–1PZ4 (9.6 kcal/mol), isoorientin–2BL9 (−8.8), and chrysin–4ZL4 (−9.6). These binding affinities were stronger than the control ligands. An analysis of the results suggests that isoorientin and chrysin could act as anti-malarial agents. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 204 KiB

Open AccessAbstract

Evaluation of the Role of Different Bottom-Up Synthesis Procedures for Carbon Dots in Their Potential as Candidates as Drug Carriers

by Diana Crista, Joaquim C. G. Esteves da Silva and Luís Pinto da Silva

Med. Sci. Forum 2022, 14(1), 125; https://doi.org/10.3390/ECMC2022-13294 - 1 Nov 2022

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Abstract

Carbon Dots (CDs) application in biomedicine has been increasing, due to their properties of high photoluminescence, biosafety and low cost, which allow for possible applications in bioimaging and as drug carriers. However, their synthesis strategies are quite flexible, as tuning-reaction precursors and synthesis [...] Read more.

Carbon Dots (CDs) application in biomedicine has been increasing, due to their properties of high photoluminescence, biosafety and low cost, which allow for possible applications in bioimaging and as drug carriers. However, their synthesis strategies are quite flexible, as tuning-reaction precursors and synthesis procedures can lead to an endless number of CDs with distinct properties and applications, which make their practical development difficult. In this work, we performed a systematic evaluation of the effect of three representative bottom-up strategies (hydrothermal, microwave-assisted and thermal heating) on the properties of CDs prepared from the same precursors (glucose and urea). In this way, the CDs were thoroughly evaluated in terms of structure, morphology and photoluminescent properties. To screen their potential as drug carriers, the biosafety of these CDs was tested against the normal breast cell line MCF-10A, as drug carriers need to be compatible with healthy cells to minimize harmful side-effects. The characterization results demonstrated a similar size range and composition for all the CDs. While hydrothermal synthesis generates CDs with lower fluorescence and synthesis yields, presenting also an emission more dependent on surface states, these CDs have the most promising viability profile in MCF-10A when compared with microwave-assisted and thermal-heating CDs, which present better fluorescence properties and. Our results suggest these CDs have the potential to proceed in further investigations in animal models as imaging candidates or biosensing tools, as well as drug carriers for future applications in medicine. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 187 KiB

Open AccessAbstract

In the Heart of Cardio-Oncology: The Targets and Biomarkers of Cardiotoxicity in Anticancer Drugs

by Vera Marisa Costa

Med. Sci. Forum 2022, 14(1), 126; https://doi.org/10.3390/ECMC2022-13157 - 1 Nov 2022

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Abstract

The cardiotoxicity of anticancer drugs is the second leading cause of death in cancer patients. Among other adverse effects, left ventricular ejection fraction decreases or heart failure emerges after anticancer treatments comprising old or new targeted therapies. In the last few years, our [...] Read more.

The cardiotoxicity of anticancer drugs is the second leading cause of death in cancer patients. Among other adverse effects, left ventricular ejection fraction decreases or heart failure emerges after anticancer treatments comprising old or new targeted therapies. In the last few years, our group has been trying to unveil the cardiac adverse outcome pathways of classic chemotherapeutic agents, mainly focusing on two topoisomerase inhibitors, mitoxantrone and doxorubicin. Mitoxantrone and doxorubicin both cause cumulative dose cardiotoxicity and were tested in vitro and in pre-clinical models. Results obtained in mice and rats following a clinically relevant dosing scheme were mimicked in vitro, demonstrating that the drugs change cellular redox homeostasis and promote inflammation, although in different biomarkers. Moreover, autophagy and energetic pathways were affected; the first mainly after mitoxantrone and the latter when doxorubicin was used. Thus, these drugs have distinct cardiac fingerprints. In conclusion, although their clinical cardiac effects are similar in humans, mitoxantrone and doxorubicin have different initiating cardiotoxic events. These were revealed taking into account the use of proper experimental models, clinically relevant concentrations, and Omics methods. These data are the essence in terms of promoting drug-specific cardioprotective measures in the future, for patients treated with these drugs. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 176 KiB

Open AccessAbstract

Sulfur [¹⁸F]Fluoride Exchange Reaction Enables Rapid Access to ¹⁸F-Labeled PET Tracers

by Austin Craig, Jürgen Kogler, Fabian Krutzek, Florian Brandt, Markus Laube, Martin Ullrich, Cornelius Kurt Donat, Klaus Kopka and Sven Stadlbauer

Med. Sci. Forum 2022, 14(1), 127; https://doi.org/10.3390/ECMC2022-13652 - 16 Nov 2022

Cited by 1 | Viewed by 1151

Abstract

Efficient ¹⁸F-fluorination procedures for the production of radiopharmaceuticals are urgently needed to satisfy the increasing demand for clinical diagnostics using positron emission tomography (PET). However, the development of PET tracers is often a time-consuming and challenging process. This work examines the applicability [...] Read more.

Efficient ¹⁸F-fluorination procedures for the production of radiopharmaceuticals are urgently needed to satisfy the increasing demand for clinical diagnostics using positron emission tomography (PET). However, the development of PET tracers is often a time-consuming and challenging process. This work examines the applicability of the recently described sulfur [¹⁸F]fluoride exchange ([¹⁸F]SuFEx) chemistry as a fast screening approach towards a number of clinically relevant PET tracer preparations. The preparation of a number of ¹⁸F-labeled compounds commenced with [¹⁸F]fluoride loading onto a quarternary methylammonium (QMA) cartridge, which was eluted with a methanolic solution containing a base, followed by solvent removal under reduced pressure. Thereafter, the radiolabeling precursors in MeCN were added to the reaction vessels, and allowed to react via [¹⁸F]SuFEx at room temperature for 5 min. The radiofluorination reactions were quenched by water dilution followed by C18 cartridge purification. The ¹⁸F-labeled products were isolated by elution from the cartridge with EtOH and the identities of the products were confirmed by radio-ultra high performance liquid chromatography (UHPLC). The optimized preparations of ¹⁸F-labeled prostate-specific membrane antigen (PSMA) inhibitor, Programmed death-ligand 1 (PD-L1) ligand, cyclooxygenase-2 inhibitor (COXIB), and Fibroblast activation protein alpha inhibitor (FAPI) were achieved with high non-decay corrected isolated activity yields (AY) of 33–57% (n = 12) and >95% radiochemical purity (RCP) in 25 min. The automated radiosynthesis procedures afforded the radiolabeled products in an unoptimized 8–15% AY (n = 5), with >95% RCP in 40 min. The ultra-fast [¹⁸F]SuFEx reaction permitted several structurally diverse ¹⁸F-labeled compounds for potential imaging to be rapidly achieved in excellent isolated AYs and high RCP. Presently, optimization of the automated radiosynthesis and biological assessment of the ¹⁸F-labeled products is underway. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Synthesis of Novel 2-Phenylindole Analogues as Antifungal and Antibacterial Agents

by Ke Yang and Xinhui Pan

Med. Sci. Forum 2022, 14(1), 128; https://doi.org/10.3390/ECMC2022-13172 - 1 Nov 2022

Viewed by 553

Abstract

A series of novel indole derivatives containing ester groups, halogen, epoxy and short-chain aliphatic hydrocarbons were designed, synthesized and evaluated for their antibacterial activities. Most of the compounds showed relatively excellent inhibitory activities against different strains (including a multidrug-resistant clinical isolate). Compounds 3f [...] Read more.

A series of novel indole derivatives containing ester groups, halogen, epoxy and short-chain aliphatic hydrocarbons were designed, synthesized and evaluated for their antibacterial activities. Most of the compounds showed relatively excellent inhibitory activities against different strains (including a multidrug-resistant clinical isolate). Compounds 3f, 3o and 3r showed the strongest inhibitory activity (mic of 2–32 μg/mL). Compounds 3f, 3h, 3i, 3o and 3r with antibacterial activity were not cytotoxic against RAW 264.7 mouse macrophages. The structure–activity relationship analysis and docking studies showed that the halogens as well as aliphatic hydrocarbons could enhance the antibacterial ability and reduce the toxicity of the indole compounds. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 181 KiB

Open AccessAbstract

Design, Synthesis, and Biological Activity of 18β-Glycyrrhetinic Acid Derivatives and Their Metal Complexes

by Caiyun Yang, Xinhui Pan and Xiaoda Yang

Med. Sci. Forum 2022, 14(1), 129; https://doi.org/10.3390/ECMC2022-13193 - 1 Nov 2022

Viewed by 609

Abstract

The increasing morbidity and mortality caused by infections with pathogenic bacteria (fungus or bacteria) have highlighted an urgent requirement for developing novel anti-bacterial agents to protect the health and integrity of human life. 18β-glycyrrhetinic acid has a wide range of pharmacological [...] Read more.

The increasing morbidity and mortality caused by infections with pathogenic bacteria (fungus or bacteria) have highlighted an urgent requirement for developing novel anti-bacterial agents to protect the health and integrity of human life. 18β-glycyrrhetinic acid has a wide range of pharmacological effects including anti-bacterial, anti-inflammatory, and anti-tumor effects. Nevertheless, its relatively low biological activity and high toxicity limit its potential for anti-bacterial and other pharmaceutical applications. To improve the anti-bacterial activity of 18β-glycyrrhetinic acid, we designed and synthesized a total of 21 glycyrrhizic acid derivatives in 40–82% yields, among which 18 novel glycyrrhetinic acid derivatives, and the anti-bacterial and anti-fungal activities of all synthesized derivatives, were evaluated in vitro by measuring the minimum inhibitory concentration (MIC) of the compounds against the strain. The evaluation results showed that most of the compounds showed good inhibitory activity against different strains, among which compound 1 (MIC: 2 μg/mL) and compound 3 (MIC: 2 μg/mL) showed the strongest anti-fungal activity against Cryptococcus; compound 20 (MIC: 4 μg/mL) showed high anti-bacterial activity against Pseudomonas aeruginosa and merits further exploration as a new anti-bacterial and anti-fungal agent. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Patient-Centric Drug Product Design: Case Studies for Special Populations

by Isabel F. Almeida

Med. Sci. Forum 2022, 14(1), 130; https://doi.org/10.3390/ECMC2022-13189 - 1 Nov 2022

Viewed by 651

Abstract

Medication non-adherence poses considerable challenges in managing chronic diseases and is associated with almost 200,000 deaths and EUR 80–125 billion in potentially preventable direct (e.g., hospitalizations, waste of medication) and indirect (e.g., work productivity losses) costs in the European Union alone. The increasing [...] Read more.

Medication non-adherence poses considerable challenges in managing chronic diseases and is associated with almost 200,000 deaths and EUR 80–125 billion in potentially preventable direct (e.g., hospitalizations, waste of medication) and indirect (e.g., work productivity losses) costs in the European Union alone. The increasing awareness of the contribution of the acceptability of drug products by the patient to medication adherence and clinical outcomes is driving the integration of patient-centric drug product design (PCDPD) into the pharmaceutical development process. Regulatory agencies have addressed the relevancy of placing the patient at the center of pharmaceutical development. The EMA has issued guidelines/reflection papers for pediatric and older populations while the FDA has developed a series of guidance documents on patient focused drug development with the primary goal to better incorporate the patient’s voice in drug development and evaluation. PCDPD can be defined as the process of identifying the comprehensive needs of the target patient population to support the design of drug products. Three major factors are analyzed in PCDPD, namely, the patient, drug, and drug product characteristics. This systematic approach integrates this insight, which is translated to a target product profile (TPP) to drive the pharmaceutical product design process. Two case studies are presented focused on the pediatric population and on patients with a chronic skin disorder (psoriasis), which will highlight the roadmap for a successful PCDPD. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 174 KiB

Open AccessAbstract

Are the Co(III) Complexes with Diamine Chelate Ligands a Response to New Antifungal Compounds?

by Katarzyna Turecka, Agnieszka Chylewska, Anna Kawiak and Krzysztof Waleron

Med. Sci. Forum 2022, 14(1), 131; https://doi.org/10.3390/ECMC2022-13231 - 1 Nov 2022

Viewed by 637

Abstract

Increasing resistance of fungi, especially Candida spp., has successively reduced the already short list of effective antifungal drugs used in clinical therapy. Thus there is an urgent need for new, non-toxic antifungals with novel modes of action. A very interesting and attractive group [...] Read more.

Increasing resistance of fungi, especially Candida spp., has successively reduced the already short list of effective antifungal drugs used in clinical therapy. Thus there is an urgent need for new, non-toxic antifungals with novel modes of action. A very interesting and attractive group of compounds seems to be complexes of Co(III) with diamine chelate ligands due to their therapeutic uses as antiviral, antibacterial, antifungal, antiparasitic, or antitumor agents. Two Co(III) complexes with diamine chelate ligands ([CoCl₂(dap)₂]Cl (1) and [CoCl₂(en)₂]Cl (2)) (where dap = 1,3-diaminopropane, en = ethylenediamine) were synthesized and characterized using elemental analysis, an ATR technique, and a scan method and sequentially tested to evaluate the mode of action. The assessment of cell damage by the newly synthetized photosensitive fluorescein-labelled complex 1 ([Co(dap)₂FLU]Cl₂) was performed using fluorescent microscopy, which indicated cell membrane permeability and altered cell morphology. The study of the C. albicans survival in blood showed a slight reduction in the number of viable, colonizing cells in the sample compared to the results obtained for the substances with confirmed antifungal activity – ketoconazole. DNA cleavage ability of the Co(III) complexes using agarose gel electrophoresis against genomic DNA isolated from a C. albicans cells showed nuclease activity for both complexes. This study provides new data on potential antifungal drugs, especially against Candida species. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Using Machine Learning-Based Hierarchical Support Vector Regression Approach to Predict Skin Permeability

by Max K. Leong and Giang Huong Ta

Med. Sci. Forum 2022, 14(1), 132; https://doi.org/10.3390/ECMC2022-13166 - 1 Nov 2022

Cited by 1 | Viewed by 623

Abstract

Skin is the largest organ in the human body, and it works as the natural barrier against the external environment. Furthermore, topical and transdermal drug delivery has emerged as a new effective and safer administration choice. A variety of in vitro, in vivo, [...] Read more.

Skin is the largest organ in the human body, and it works as the natural barrier against the external environment. Furthermore, topical and transdermal drug delivery has emerged as a new effective and safer administration choice. A variety of in vitro, in vivo, and ex vivo assays have been adopted to evaluate the retention of the drug in the skin layers and the skin permeability, in which the ex vivo excised human skin has been considered as the gold standard to assess the skin penetration despite its potential for ethical issues. In this study, the novel machine learning-based hierarchical support vector regression (HSVR) was adopted to generate a nonlinear quantitative structure–activity relationship (QSAR) model, which can predict the Kp values based on the ex vivo human skin permeability data. The HSVR model showed a consistent performance with the experimental data and among the training set, test set, outlier set, and mock test, which was designated to mimic the real challenges. In addition, the HSVR exhibited a better prediction performance than the classical partial least squares (PLS) did. Thus, it can be concluded that the novel HSVR model can be utilized to facilitate the assessment of the skin permeability of the novel compounds in drug discovery. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 205 KiB

Open AccessAbstract

Design, Synthesis, and Biological Evaluation of New Benzoxaborole Derivatives as Potential Antimycobacterial Agents

by Petr Šlechta, Ondřej Jand’ourek, Klára Konečná, Pavla Paterová, Pavel Bárta, Vladimír Kubíček, Martin Doležal and Marta Kučerová-Chlupáčová

Med. Sci. Forum 2022, 14(1), 133; https://doi.org/10.3390/ECMC2022-13454 - 1 Nov 2022

Viewed by 681

Abstract

The current study is focused on the combination of pyrazinamide with 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol, which is a crucial pharmacophore of several antimicrobial agents. The use of benzoxaborole moiety could afford the formation of a spiro adduct between benzoxaborole moiety and 3'-terminal adenosine nucleotide [...] Read more.

The current study is focused on the combination of pyrazinamide with 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol, which is a crucial pharmacophore of several antimicrobial agents. The use of benzoxaborole moiety could afford the formation of a spiro adduct between benzoxaborole moiety and 3'-terminal adenosine nucleotide Ade76 of tRNA^Leu. In the form of this spiro adduct, it may potentially inhibit the enzyme leucyl-tRNA synthetase (LeuRS). A large heterocyclic substitution in position 6 of the benzoxaborole moiety could lead to the enhanced selectivity of the intended compounds to the bacterial enzyme due to steric clashes with eukaryotic types of LeuRS. The target compounds were synthesized by condensation of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol with variously substituted heteroaromatic acids that underwent previous activation. The synthetic products and the isolated condensation intermediates were subjected to biological in vitro screening against fungi and bacteria, including mycobacteria and in vitro cytotoxicity screening against the HepG2 cancer cell line. Some of the compounds showed moderate antimycobacterial activity with persisted low toxicity. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 174 KiB

Open AccessAbstract

Exploratory Studies on Anticancer Potential of a Vernonia Species against Colorectal Adenocarcinoma: In Vitro Studies and In Silico Mechanistic Investigations

by Radhika K. Raheja and Arundhati Nachiket Abhyankar

Med. Sci. Forum 2022, 14(1), 134; https://doi.org/10.3390/ECMC2022-13456 - 1 Nov 2022

Viewed by 638

Abstract

Globally, colorectal cancer (CRC) is amongst the most prevalent cancer incidences, being the second most common amongst women and third most common amongst men as revealed by ‘GLOBOCAN 2022’ statistics. The projected morbidity for CRC is more than 3 million by the year [...] Read more.

Globally, colorectal cancer (CRC) is amongst the most prevalent cancer incidences, being the second most common amongst women and third most common amongst men as revealed by ‘GLOBOCAN 2022’ statistics. The projected morbidity for CRC is more than 3 million by the year 2040 according to the ‘WHO Cancer Tomorrow’ predictions. Surgery, chemotherapy, and radiation therapy continue to be the primary treatment options, each with particular limitations. There is a growing need for identification of alternate therapies for the treatment of colorectal cancer to overcome the shortfalls of these treatment options. Phytoconstituents offer diverse pharmacophoric scaffolds with unique chemical features. In this work, successive extracts of aerial plant parts of a Vernonia species (family Asteraceae) have been screened in vitro on colorectal adenocarcinoma cell lines Colo205 and HT-29 by MTT assay and compared with 5-Flurouracil as the reference standard. The plant is known to possess triterpenoids, quaternary alkaloids, phenolics, and sesquiterpene lactones. In silico docking studies have been carried out on the plausible phytoconstituents of the active extracts against vital protein targets involved in the progression of CRCs, such as cyclin-dependent kinases, and enzymes of apoptotic pathways, such as caspases, etc. These studies will help to discover the mechanistic details of the anticancer activity of the plant and will provide a platform for the development of novel multi-targeted small molecules. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 185 KiB

Open AccessAbstract

Development of In Situ Gel Containing Phytoconstituents for the Treatment of Mouth Ulcers

by Kevinkumar Garala and Parag Rabara

Med. Sci. Forum 2022, 14(1), 135; https://doi.org/10.3390/ECMC2022-13438 - 1 Nov 2022

Viewed by 806

Abstract

An ulcer that develops on the mucosal surface of the oral cavity is known as a mouth ulcer, also known as an oral ulcer or a mucosal ulcer. A mucus membrane ulcer is an open sore that is distinguished by the removal of [...] Read more.

An ulcer that develops on the mucosal surface of the oral cavity is known as a mouth ulcer, also known as an oral ulcer or a mucosal ulcer. A mucus membrane ulcer is an open sore that is distinguished by the removal of inflammatory dead tissue. The most typical type of oral ulcer is aphthous stomatitis. This investigation focuses on temperature-sensitive in situ gel formulations, which change their phase in response to body heat from liquid to semisolid gel. These are easily administered into the buccal cavity at the ulcer site and are a free-flowing liquid at room temperature. Utilizing various polymers, a temperature-sensitive in situ gel comprising phytoconstituents was developed utilising the cold technique. To optimise various types and concentrations of polymers, including carbopol, Poloxamer 188 (P 188), Poloxamer 407 (P 407), and others, preliminary research was conducted. For the formulation, 20% P 188 and 15% P 407 were employed because there is a correlation between the amount of poloxamers and thermogelling transition temperatures (Tsol-gel). A blend of phytoconstituents found in the extracts of Glycyrrhizin glabra and Psidium guava is used in the formulation of mouth ulcers because, as we know, they have fewer negative effects than synthetic chemicals. The outcomes demonstrated improved homogeneity, stability, gelation temperature, and spreadability for the developed product, which was regarded as satisfactory. The created formulation can also lessen dose variation and treat oral ulcers in the most effective way, with improved patient compliance. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 199 KiB

Open AccessAbstract

Box–Behnken Assisted HPLC Development of Simultaneous Determination of Doxorubicin and Vorinostat Encapsulated into Polymeric Nanoparticles

by Maria Sokol, Ivan Gulyaev, Mariia Mollaeva, Sergey Kuznetsov, Vladimir Zenin, Maksim Klimenko, Nikita Yabbarov, Margarita Chirkina and Elena Nikolskaya

Med. Sci. Forum 2022, 14(1), 136; https://doi.org/10.3390/ECMC2022-13493 - 7 Nov 2022

Cited by 1 | Viewed by 617

Abstract

The objects of the present study are nanoparticles (NPs) based on a copolymer of lactic and glycolic acids (PLGA), loaded with the anticancer drug doxorubicin (DOX-NP) and histone deacetylase inhibitor vorinostat (SAHA-NP) and developed for breast cancer treatment [...] Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 170 KiB

Open AccessAbstract

Extraction of Anthocyanins from Black Currants and In Vitro Testing for the Determination of Antioxidant Activity

by Veronica Popa, Sorin Avramescu and Miruna Silvia Stan

Med. Sci. Forum 2022, 14(1), 137; https://doi.org/10.3390/ECMC2022-13146 - 1 Nov 2022

Viewed by 665

Abstract

Black currants have antioxidant, anti-inflammatory and chemoprotective properties. Anthocyanins, which are components of black currants, are powerful antioxidants that are able to inhibit the growth of tumor cells and induce apoptosis. In this context, our study was designed to investigate the antitumoral effects [...] Read more.

Black currants have antioxidant, anti-inflammatory and chemoprotective properties. Anthocyanins, which are components of black currants, are powerful antioxidants that are able to inhibit the growth of tumor cells and induce apoptosis. In this context, our study was designed to investigate the antitumoral effects following exposure to the total ethanolic extract obtained from blackcurrant powder, rich in anthocyanins, on cervical cancer. The content of total phenolic compounds was analyzed using Folin-Ciocalteu reagent, and the concentration of anthocyanins was determined by HPLC. The in vitro characterization of the extracts included common tests to measure antioxidant capacity, cell viability and inflammation tests on HeLa cervix cells, and measure reduced glutathione level and catalase and glutathione S-transferase activities, as well as flow cytometry analysis to evaluate the cell cycle phases. Our study demonstrated that the extract with the highest concentration in anthocyanins (delphinidin and malvidin), with an antiproliferative capacity, was the one obtained after 48 h of extraction with ethanol, which induced a time- and dose-dependent decrease in cancer cell viability. An increase in enzyme activity of catalase and glutathione S-transferase was noted after the first 24 h of incubation, suggesting a tendency of the cells to counteract the oxidative stress induced by anthocyanins. Incubation of cells with blackcurrant extract resulted in cell cycle arrest in the G1 and sub-G1 phases after 24 and 72 h, respectively. These data support the antioxidant and antiproliferative efficiency of anthocyanins from black currants, which is valuable for further in vivo studies. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 180 KiB

Open AccessAbstract

Annonaceous Acetogenins Reported for the First Time in the Leaves and Fruit’s Pulp of Annona atemoya

by Bassam S. M. Al Kazman, Joanna E. Harnett and Jane Rouse Hanrahan

Med. Sci. Forum 2022, 14(1), 138; https://doi.org/10.3390/ECMC2022-13444 - 1 Nov 2022

Viewed by 730

Abstract

Annona atemoya is a commercially important fruiting plant belonging to the Annonaceae family. It is widely cultivated in tropical and subtropical continents. It is also known as the custard apple which is a hybrid between two Annonaceae species, those being Annona cherimola and [...] Read more.

Annona atemoya is a commercially important fruiting plant belonging to the Annonaceae family. It is widely cultivated in tropical and subtropical continents. It is also known as the custard apple which is a hybrid between two Annonaceae species, those being Annona cherimola and Annona squamosa. This study aimed to investigate the phytochemical constituents and pharmacological activity of various parts of A. atemoya including leaves and fruit’s pulp. The leaves and fruits of A. atemoya were collected in July 2020 from a local farm in Queensland, air dried at room temperature (3 days–1 week) and then ground to a powder. The leaves and pulp were separately extracted with hexane, ethyl acetate and finally ethanol for three days each. The preliminary results of Thin layer chromatography (TLC) and Nuclear magnetic resonance (NMR) experiments indicated the presence of annonaceous acetogenins for the first time in the leaves and pulp as pink bands after reacting with Kedde reagent. For the leaves, ten compounds were identified, two of them were isolated and the other confirmed via NMR and MS analysis. The ethyl acetate extract of leaf was the richest in an abundance of acetogenins in comparison to the hexane extract. With regards to the fruit’s pulp, the concentration of acetogenins was very low compared to the leaves. Future studies will focus on testing either isolated compounds or crude extracts using various cancer cell lines. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 200 KiB

Open AccessAbstract

The Synthesis and Biological Activity of Amidrazone Derivatives Obtained in Reaction with cis-1,2,3,6-Tetrahydrophthalic Anhydride

by Renata Paprocka, Małgorzata Wiese-Szadkowska, Jolanta Kutkowska and Adam Kowalewski

Med. Sci. Forum 2022, 14(1), 139; https://doi.org/10.3390/ECMC2022-13453 - 1 Nov 2022

Viewed by 818

Abstract

Amidrazones are known for the broad biological activity of their derivatives (antimicrobial, anti-inflammatory, antiparasitic, antitumor and others). While searching for new drugs, twelve new derivatives of N³-substituted amidrazones were obtained in the reaction with cis-1,2,3,6-tetrahydrophthalic anhydride. The structures of obtained [...] Read more.

Amidrazones are known for the broad biological activity of their derivatives (antimicrobial, anti-inflammatory, antiparasitic, antitumor and others). While searching for new drugs, twelve new derivatives of N³-substituted amidrazones were obtained in the reaction with cis-1,2,3,6-tetrahydrophthalic anhydride. The structures of obtained linear compounds and 1,2,4-triazole derivatives were confirmed by ¹H NMR, ¹³C NMR and MS. Toxicity and inflammatory activity of obtained compounds (at concentrations of 10, 50 and 100 µg/mL) were studied in human peripheral blood mononuclear cells (PBMC). The influence of new derivatives on cytokine production (TNF-α, IL-6 and IL-10) was examined in PBMC cultures stimulated by LPS. Antiproliferative activity of compounds was studied in PBMC cultures stimulated by phytohaemagglutinin. Minimal inhibitory activity of compounds was studied by broth microdilution method on Gram-positive (S. aureus, M. smegmatis) and Gram-negative (E. coli, Y. enterocolitica, K. pneumonia) bacterial and fungal C. albicans strain. Obtained 1,2,4-triazole derivatives were not toxic to PBMC at a concentration range of 10–100 µg/mL. Only one 1,2,4-triazole derivative showed significant antiproliferative activity at the highest dose. Five 1,2,4-triazole derivatives showed significant, stronger than ibuprofen, inhibition of pro-inflammatory TNF-α production at concentrations 10 and 50 µg/mL, as well as significant elevation of levels of anti-inflammatory cytokine IL-10 at each used dose. Two linear compounds showed antibacterial activity against Gram-positive bacteria. In conclusion, five obtained compounds showed a strong anti-inflammatory effect and deserve further research. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 175 KiB

Open AccessAbstract

Targeted Delivery of Doxorubicin to Breast Cancer Cells by Multiwalled Carbon Nanotubes Functionalized with Lysine via 1,3-Dipolar Cycloaddition and Conjugation with Sugar Moieties

by Chanchal Kiran Thakur, Chandrabose Karthikeyan, Subhasmita Bhal, Chanakya Nath Kundu and Narayana Subbiah Hari Narayana Moorthy

Med. Sci. Forum 2022, 14(1), 140; https://doi.org/10.3390/ECMC2022-13421 - 1 Nov 2022

Cited by 1 | Viewed by 709

Abstract

Multiwalled carbon nanotubes (MWCNTs) have attracted considerable multidisciplinary interest and biomedical applications, such as drug delivery, because of their distinct physicochemical characteristics. The biomedical application of MWCNTs is limited by their low dispersibility in aqueous or non-aqueous mediums. Functionalizing MWCNTs is an effective [...] Read more.

Multiwalled carbon nanotubes (MWCNTs) have attracted considerable multidisciplinary interest and biomedical applications, such as drug delivery, because of their distinct physicochemical characteristics. The biomedical application of MWCNTs is limited by their low dispersibility in aqueous or non-aqueous mediums. Functionalizing MWCNTs is an effective way to overcome this drawback as it improves biocompatibility and also facilitate ligand attachment for targeted drug delivery. However, most functionalization approaches involve hazardous procedures and expensive chemicals. The current study employs a simple, cost-effective technique to functionalize MWCNTs with lysine by 1,3-dipolar cycloaddition for improved dispersibility and to provide a ligand anchoring ε-amino group for targeted delivery to breast cancer. MWCNTs had been functionalized with lysine and sugar moieties ligands (galactose/mannose) to formulate efficient nanocarriers that can bind to lectin receptors in MDA-MB-231 or MCF-7 cancer cells. Doxorubicin (Dox) was loaded into the ligands conjugated MWCNTs. In comparison to pristine MWCNTs, 1,3-lysinated MWCNTs conjugated with ligands demonstrated enhanced dispersion in aqueous medium and a greater drug loading capacity. In drug release studies MWCNTs were found to exhibit pH-dependent drug release, releasing 20% of the drug at pH 7.4, and 75% at pH 5.0. Dox-loaded MWCNTs also enhanced Dox accumulation inside the cancer cells, as evidenced by higher inhibition of MDA-MB-231 or MCF-7 proliferation compared to plain Dox, and unloaded Dox MWCNTs. The findings suggest that MWCNTs functionalized with lysine by 1,3-dipolar cycloaddition provide a potentially nontoxic nanoplatform with enhanced aqueous dispersibility and the potential for conjugation with ligands for the targeted delivery of Dox to breast cancer cells.. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 189 KiB

Open AccessAbstract

β-Cyclodextrins as Carriers for the Targeted Delivery of Pharmaceutical Substances against Lipase from Malassezia spp.

by Viktor Andreevich Filatov

Med. Sci. Forum 2022, 14(1), 141; https://doi.org/10.3390/ECMC2022-13497 - 7 Nov 2022

Viewed by 1004

Abstract

Seborrheic dermatitis (SD) and dandruff are the most prevalent scalp diseases in populations around the world. The main etiopathogenetic factor of these diseases is an altered abundance of Malassezia species that secrete several lipases and turn acylglycerides into fatty acids associated with an [...] Read more.

Seborrheic dermatitis (SD) and dandruff are the most prevalent scalp diseases in populations around the world. The main etiopathogenetic factor of these diseases is an altered abundance of Malassezia species that secrete several lipases and turn acylglycerides into fatty acids associated with an inflammatory reaction, itching, and scalp dryness. The investigated synthetic and natural-based agents showed activity against Malassezia lipase, but they have low solubility and therefore bioavailability. β-cyclodextrins (β-CDs) and their derivatives are promising carriers and additives with which to improve the solubility of molecules and carry out possible targeted drug delivery. Therefore, this research aimed to evaluate the β-CD–lipase interaction as well as the influence of β-CDs on lipase activity. Modern methods are used to model the structural elucidation of β-CDs with lipase. In this study, transmission electron microscopy (TEM) showed that β-CD–lipase complexes were formed in the form of grape bunches to maintain stability. Additionally, β-CDs interacted with the active site and terminal subunits of lipase. Moreover, β-CDs changed the configuration of lipase in a dose-dependent manner, identified by UV spectroscopy and fluorescence assays. Furthermore, lipase activity, measured by oleic acid yield, was significantly decreased due to the presence of different β-CD concentrations. Thus, β-CDs strongly interacted with lipase and influenced its enzymatic activity, meaning that they could be considered as drug delivery systems for novel therapies of SD and dandruff. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 194 KiB

Open AccessAbstract

Palladium-Spermine Complex (Pd₂Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells

by Martin Vojtek, Maria P. M. Marques, Ana L. M. Batista de Carvalho, Helder Mota-Filipe, Isabel M. P. L. V. O. Ferreira and Carmen Diniz

Med. Sci. Forum 2022, 14(1), 142; https://doi.org/10.3390/ECMC2022-13469 - 1 Nov 2022

Viewed by 775

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast carcinoma with a poor prognosis. Current treatment options with platinum-(Pt)-based chemotherapeutics are limited by toxicity/acquired resistance, which has prompted the search for novel metal-based compounds. Dinuclear palladium(II)-spermine chelate (Pd₂Spm) has previously shown promising [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive breast carcinoma with a poor prognosis. Current treatment options with platinum-(Pt)-based chemotherapeutics are limited by toxicity/acquired resistance, which has prompted the search for novel metal-based compounds. Dinuclear palladium(II)-spermine chelate (Pd₂Spm) has previously shown promising pharmacokinetics and in vivo antitumor effects. However, its impact on chemotherapy-resistant TNBC is still to be addressed. This work developed a cell model of cisplatin resistance and compared the anticancer/antiproliferative effects of cisplatin (reference Pt-based drug) and Pd₂Spm in TNBC cells sensitive (MDA-MB-231) and resistant to cisplatin (MDA-MB-231/R). Pd₂Spm displayed a similar antiproliferative potency in MDA-MB-231 and MDA-MB-231/R cells, while cisplatin showed ca. 18-fold lower potency towards MDA-MB-231/R cells. When focusing on cell death, the incubation of Pd₂Spm with either necrostatin-1 (necroptosis inhibitor), Z-VAD (apoptosis inhibitor), or 3-methyladenine (3-MA, autophagy inhibitor) showed that 3-MA could rescue Pd₂Spm-induced growth inhibition in MDA-MB-231 and MDA-MB-231/R cells. Furthermore, in MDA-MB-231 cells, Pd₂Spm triggered higher LC3-II levels and more profound Beclin-1 inhibition than cisplatin. Regarding apoptosis, Pd₂Spm did not induce the cleavage of caspase-3, and the co-incubation of both Pd₂Spm and Z-VAD yielded only marginal effects in preventing phosphatidylserine externalization compared to cisplatin. Thus, the present data provide more evidence on Pd₂Spm’s cell death mechanisms, which trigger a caspase-independent cell death with autophagy involvement. In addition, the potential of Pd₂Spm to overcome chemotherapy resistance is promising. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 188 KiB

Open AccessAbstract

Design, Synthesis, Molecular Docking Studies, and Biological Evaluation of 1, 3, 4-oxadiazol-3(2H)-yl] Ethan-1-one Derivatives as Antimicrobial Agents

by Rupali Likhar and Tabassum Khan

Med. Sci. Forum 2022, 14(1), 143; https://doi.org/10.3390/ECMC2022-13247 - 1 Nov 2022

Viewed by 721

Abstract

A number of novel 1, 3, 4-oxadiazole analogues have been designed and synthesized through the condensation of substituted aldehyde/ketone with substituted benzohydrazide to form substituted N′-alkylidene benzohydrazide and then cyclization of N′-alkylidene benzohydrazide to form 1, 3, 4-oxadiazole derivatives. To investigate [...] Read more.

A number of novel 1, 3, 4-oxadiazole analogues have been designed and synthesized through the condensation of substituted aldehyde/ketone with substituted benzohydrazide to form substituted N′-alkylidene benzohydrazide and then cyclization of N′-alkylidene benzohydrazide to form 1, 3, 4-oxadiazole derivatives. To investigate the antimicrobial data on a structural basis, in-silico docking studies of the synthesized compounds (4a–4r) into the crystal structure of E. coli DNA gyrase (Type-2 topoisomerase) using Autodock PyRx virtual screening program were performed to predict the affinity and orientation of the synthesized compounds at the activities by using 6rks Protein Data Bank (PDB). Inhibiting the ATPase activity of gyrase blocks the introduction of negative supercoils in DNA and traps the chromosome in a positively supercoiled state that may have a downstream impact on cell physiology and division. The results indicate that ketone-substituted benzohydrazide derivatives show good binding affinity (−8 kcal to −9 kcal) and electron-withdrawing group such as –NO₂ and –Cl present at R1 increases the affinity of scaffold and DNA gyrase receptors and binds into the specificity pocket. In this pocket, the 1, 3, 4-oxadiazole nucleus of these compounds interacts with the amino acid Alanine A: 421, Valine A: 420, Tyrosine A: 478, and Glutamine A: 381 residues of the target. Also, it is verified by in vitro antimicrobial screening, where all the compounds were active against tested bacterial strains. Among these compounds 4(c), 4(d), (4e), (4h), (4i), 4(m), 4(n), 4(o), 4(p), and (4q) showed good bacterial zone inhibition. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 207 KiB

Open AccessAbstract

Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation

by Gabrielle Bangay, Vera M. S. Isca, Daniel J. V. A. Dos Santos, Ricardo J. Ferreira, Salvatore Princiotto, Mirna Jovanovic, Milica Pesic and Patricia Rijo

Med. Sci. Forum 2022, 14(1), 144; https://doi.org/10.3390/ECMC2022-13459 - 1 Nov 2022

Viewed by 694

Abstract

The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise, such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), or the selective modulation of protein [...] Read more.

The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise, such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), or the selective modulation of protein kinases C (PKC) isoforms continues to be a major impediment to effective therapy. Known for their medicinal properties, species from Plectranthus have been reported to have cytotoxicity against various cancer cell lines due to diterpenes, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6,7-dehydroroyleanone (DeRoy). Based on molecular docking simulations, 10 semi-synthetic derivatives of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was demonstrated that three abietane diterpenoids induced P-gp inhibition in MDR cancer cell lines. As regards the PKC activity, further analogues were tested as PKC (α, βI, δ, ε and ζ) modulators; one benzoylated derivative showed the ability to selectively activate PKC-δ, while the natural compound DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms. Further investigations are ongoing to prepare analogues of other biologically active diterpenoids to obtain potential hits as P-gp and PKC modulators. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 174 KiB

Open AccessAbstract

Testing the Suitability of Preserved Insect Collections for Biodiscovery Using Liquid Chromatography Mass Spectrometry

by Sundara M. U. P. Mawalagedera, Cecile Gueidan, Matthew Taylor, Andrew C. Warden and Juanita Rodriguez

Med. Sci. Forum 2022, 14(1), 145; https://doi.org/10.3390/ECMC2022-12914 - 26 Sep 2022

Viewed by 716

Abstract

Small metabolites and venom metabolites produced by insects are known to exhibit biological activity. These metabolites could be used to develop natural product-based therapeutics. To screen for these metabolites, insects must be collected and accurately identified. Natural history collections consist of identified insects [...] Read more.

Small metabolites and venom metabolites produced by insects are known to exhibit biological activity. These metabolites could be used to develop natural product-based therapeutics. To screen for these metabolites, insects must be collected and accurately identified. Natural history collections consist of identified insects and provide a source of raw material for metabolomic screening. The objective of this research was to understand whether preservation significantly altered the insect metabolomic profiles. Insects from the family Sphecidae: Podalonia tydei (Le Guillou), which were preserved in ethanol, flash frozen, and homogenized with methanol. The resulting metabolomic extracts and storage ethanol were analysed using untargeted liquid chromatography-mass spectrometry. Mass spectral data were processed with MZmine2. The data were analysed using multivariate statistical analysis. In the Principal Component Analysis, ethanol stored samples and their storage solvents clustered close together. This was verified by Analysis of Similarity (ANOSIM). Based on ANOSIM (p = 0.003, R² = 0.48), there was significant overlap between chemical profiles of treatments (ethanol only, ethanol stored tissue, flash frozen tissue). A group of acyl-carnitines were putatively identified from the extracts. The flash frozen samples have a high relative abundance for acyl-carnitines, however the Kruskal–Wallis (p > 0.05) showed no significant difference between the median of abundance. Therefore, preserved insects from natural history collections and their ethanol storage solvents could be used for metabolomic screening. However, it would be best to use specimens from the same species preserved under various conditions to capture metabolites that may degrade or leach during preservation. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 194 KiB

Open AccessAbstract

Adenosine Overcomes Triple-Negative Breast Cancer Resistance to Platinum-Derived Chemotherapeutic Drugs

by Ana Cerquido, Martin Vojtek, Olga Viegas, Patricia Dias-Pereira and Carmen Diniz

Med. Sci. Forum 2022, 14(1), 146; https://doi.org/10.3390/ECMC2022-13458 - 2 Nov 2022

Viewed by 1116

Abstract

Triple-negative breast cancer (TNBC), a poor survival cancer has high resistance to therapy, with low-drug efficacy. Adenosine is present in high concentrations in the tumor microenvironment. Recently, adenosine was found to sensitize ovarian cisplatin-resistant cancer. This work aims at addressing if adenosine can [...] Read more.

Triple-negative breast cancer (TNBC), a poor survival cancer has high resistance to therapy, with low-drug efficacy. Adenosine is present in high concentrations in the tumor microenvironment. Recently, adenosine was found to sensitize ovarian cisplatin-resistant cancer. This work aims at addressing if adenosine can sensitize TNBC resistance to platinum drugs. Concomitant or preincubation of adenosine with cisplatin or carboplatin induced cell proliferation in TNBC cisplatin-sensitive (MDA) and -resistant (MDA/R) cells (using Lionheart-FX microscope). Phosphorylation of the ERK or NF-κB pathways and cAMP production were evaluated (AlphaScreen assays). Data were analyzed with a one-way ANOVA t-test. Results: concomitant or preincubation of adenosine (300, 600, 700 µM) with cisplatin reduced resistance in MDA/R cells, with proliferation levels approaching those observed in MDA cells. In MDA cells, endogenous and exogenous adenosine have no effect over ERK phosphorylation; in MDA/R cells, exogenous adenosine lowers ERK phosphorylation. NF-κB phosphorylation was induced by A₃R and A_2BR tonic activation in MDA and MDA/R cells, respectively, increasing survival—exogenous adenosine inactivates this. Tonic cAMP production was altered in MDA and MDA/R cells, revealing inhibitory and stimulatory effects in cAMP production by A₁R and A_2BR, respectively, in MDA/R cells. In contrast, exogenous adenosine revealed that adenosine receptors in MDA cells contribute differently while in MDA/R cells all receptor subtypes have a similar contribution to cAMP production. Thus, adenosine contributes to overcome platinum-derived resistance in TNBC, involving the inactivation of the NF-κB pathway and decrease in ERK phosphorylation (partially mediated by A₃R). Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 225 KiB

Open AccessAbstract

The Iridoids of In Vitro Propagated Nepeta cyrenaica Quézel & Zaffran

by Ana Alimpić Aradski, Danijela Mišić, Uroš Gašić, Slađana Todorović, Mariana Oalđe Pavlović, Petar D. Marin, Abdulhamed Giweli and Sonja Duletić-Laušević

Med. Sci. Forum 2022, 14(1), 147; https://doi.org/10.3390/ECMC2022-13148 - 1 Nov 2022

Viewed by 590

Abstract

Nepeta cyrenaica Quézel & Zaffran (Lamiaceae), an endemic species of the Libyan flora, has been scarcely explored until now. Since Nepeta species are proven as pharmacologically active plants rich in iridoid monoterpenes, this study was aimed to quantify the iridoids present in different [...] Read more.

Nepeta cyrenaica Quézel & Zaffran (Lamiaceae), an endemic species of the Libyan flora, has been scarcely explored until now. Since Nepeta species are proven as pharmacologically active plants rich in iridoid monoterpenes, this study was aimed to quantify the iridoids present in different extracts of in vitro propagated N. cyrenaica. The seeds collected from their natural habitat were germinated. One node stem explant of 5-week-old plants were used for plant micropropagation. After several cycles, the shoots were harvested. The extraction was performed using maceration procedure by dichloromehane, methanol, 96% ethanol, and hot distilled water. Subsequently, the extracts were subjected to UHPLC/(±)HESI-MS2 analysis of iridoids. Two iridoids were identified and quantified, namely epideoxyloganic acid and nepetalactol, as well as their precursor 8-oxogeranial. Iridoid glucoside epideoxyloganic acid was the most abundant in the methanolic and ethanolic extracts (1255.37 and 1262.78 µg/100 g dry extract), followed by aqueous extract. On the other hand, 8-oxogeranial and nepetalactol reached maximal amounts in the dichloromethane extract (476.80 and 1039.52 µg/100 g dry extract, respectively). The results of this study indicate that the high antioxidant and enzyme-inhibiting effects of dichloromethane extract confirmed in our previous study could be attributed to its iridoid content, which was particularly high due to the low polarity of this extraction solvent. In conclusion, endemic N. cyrenaica could be efficiently propagated in vitro as an iridoid-rich plant with great biological potential. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 205 KiB

Open AccessAbstract

Synthesis of New Purine Nucleosides as potential Metal Chelators and Anticholinesterase Agents

by Catarina Maria, João Barros, Nuno Xavier, Karina Shimizu, Adilson Freitas, Mª João Ferreira, Ignazio Schino, Mariangela Cantore, Modesto de Candia, Nicola Colabufo, José Nuno Canongia Lopes and Amélia Rauter

Med. Sci. Forum 2022, 14(1), 148; https://doi.org/10.3390/ECMC2022-13451 - 1 Nov 2022

Viewed by 630

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by multiple factors, such as the progressive decline in the levels of the neurotransmitter acetylcholine, and the deregulation of the homeostasis of bio-metals, such as copper, zinc and iron. Acetylcholine is hydrolyzed by acetylcholinesterase and [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by multiple factors, such as the progressive decline in the levels of the neurotransmitter acetylcholine, and the deregulation of the homeostasis of bio-metals, such as copper, zinc and iron. Acetylcholine is hydrolyzed by acetylcholinesterase and butyrylcholinesterase and the current therapeutic strategies are based on the treatment of AD patients with these enzymes’ inhibitors. Although these strategies are focused on symptomatic relief of the disease, recent studies have shown that the long-term use of these drugs may lead to disease-modifying benefits. The deregulation of the bio-metals’ homeostasis has been related to oxidative stress and to the induction of Ab aggregation and tau hyperphosphorylation and aggregation. Since AD is a multifactorial disease, discovering a multi-target drug could be an interesting challenge, leading to a disease-modifying therapy. In this context, mannosylpurines synthesized by our group have already shown potent butyrylcholinesterase (BChE) inhibition. Aiming at the discovery of multitarget drug candidates, we have synthesized a new series of mannosyl and rhamnosylpurines and evaluated copper chelation and cholinesterase inhibition. The results obtained will be presented and discussed. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

1 pages, 168 KiB

Open AccessAbstract

A Potential Blueprint for the Design of Biased Ligands for Aminergic GPCRs

by Marcel Bermudez

Med. Sci. Forum 2022, 14(1), 149; https://doi.org/10.3390/ECMC2022-13487 - 2 Nov 2022

Viewed by 935

Abstract

G protein-coupled receptors (GPCRs) are omnipresent in the regulation of physiological processes and therefore account for the most prominent drug target class. However, nearly all drugs targeting GPCRs have been developed by the concept of receptors as simple on–off switches. This is surprising, [...] Read more.

G protein-coupled receptors (GPCRs) are omnipresent in the regulation of physiological processes and therefore account for the most prominent drug target class. However, nearly all drugs targeting GPCRs have been developed by the concept of receptors as simple on–off switches. This is surprising, because specifically addressing a distinct intracellular signaling pathway holds the potential to develop safer and more efficient drugs. In recent years, more and more ligands have been reported that shift the naturally imprinted preference of a receptor’s signaling profile, so-called biased ligands. It has been demonstrated for several aminergic GPCRs that an extension of their molecular structure towards extracellular receptor regions results in biased signaling. The underlying mechanism is a specific interference with the allosteric coupling mechanism by which extra- and intracellular sides of the receptor are conformationally linked. We propose a potential blueprint for the design of biased ligands based on the concept of specific interference with the extracellular receptor region and a restriction of its conformational space by extended ligand structures. While this design concept will likely identify new biased ligands, it remains a challenge to specifically design ligands with a desired signaling profile. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 195 KiB

Open AccessAbstract

Cyclodextrin-Based Cryogels for Controlled Drug Delivery

by Chiara Zagni, Alessandro Coco, Vincenzo Patamia, Giuseppe Floresta, Giusy Curcuruto, Katia Mangano, Tommaso Mecca, Antonio Rescifina and Sabrina Carroccio

Med. Sci. Forum 2022, 14(1), 150; https://doi.org/10.3390/ECMC2022-13449 - 1 Nov 2022

Cited by 1 | Viewed by 694

Abstract

Cryogels are macroporous hydrogels prepared by cryo-gelation: a green technique that involves radical polymerization using water as a solvent [...] Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

2 pages, 186 KiB

Open AccessAbstract

Optimization of Lipid-Based Ceftriaxone Delivery System via Machine Learning

by Daniela R. P. Loureiro, José X. Soares, Cláudia Nunes, Carlos M. M. Afonso and Salette Reis

Med. Sci. Forum 2022, 14(1), 151; https://doi.org/10.3390/ECMC2022-13415 - 1 Nov 2022

Cited by 1 | Viewed by 695

Abstract

Ceftriaxone (CTX) a third-generation cephalosporin, is a broad-spectrum antibiotic that can be administered via intramuscular or intravenous routes to treat various types of infection. However, CTX has poor cellular penetration and poor diffusion due to its high molecular weight and high hydrophilicity. To [...] Read more.

Ceftriaxone (CTX) a third-generation cephalosporin, is a broad-spectrum antibiotic that can be administered via intramuscular or intravenous routes to treat various types of infection. However, CTX has poor cellular penetration and poor diffusion due to its high molecular weight and high hydrophilicity. To address these problems, we propose an innovative nanotherapy based on the encapsulation of CTX in a nanostructured lipid carrier. Usually, several attempts must be made, on a trial-and-error basis, before a formulation that guarantees high drug encapsulation and suitable physicochemical properties is found. Machine Learning (ML) has recently stirred great interest as a tool to model and predict nanoparticles’ biological activity. Herein, for the first time, the use of ML for the optimization of a nanoformulation is explored. Several variables were optimized simultaneously, namely, the amount of solid lipid, the percentage of liquid lipid, the surfactant solution, the water volume, the sonication amplitude, and the sonication time. To define the best nanoformulation, three different outcomes were considered: the encapsulation efficiency of CTX, the size of the nanoparticles, and their zeta potential. Our ML approach was able to find, with a low number of experiments, the conditions that provided formulations with the highest encapsulation efficiency of CTX and nanoparticles with suitable size and adequate zeta potential. Besides the impressive acceleration of the optimization process that was achieved, the optimization guided by our ML model also provided insights into the optimization of other nanoformulations. Full article

(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)

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