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4 pages, 191 KiB

Open AccessEditorial

Designing Next-Generation Drug-like Molecules for Medicinal Applications

by Imtiaz Khan and Sumera Zaib

Molecules 2023, 28(4), 1860; https://doi.org/10.3390/molecules28041860 - 16 Feb 2023

Cited by 2 | Viewed by 1793

Abstract

The development of new drugs/drug candidates for medical treatment remains an exciting but challenging process as only a limited number of synthetic compounds fit well into the discovery and development process after multiple experiments and screening for their preclinical properties [...] Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

Research

Jump to: Editorial, Review

20 pages, 6841 KiB

Open AccessArticle

Ring-Modified Histidine-Containing Cationic Short Peptides Exhibit Anticryptococcal Activity by Cellular Disruption

by Komal Sharma, Shams Aaghaz, Indresh Kumar Maurya, Shreya Singh, Shivaprakash M. Rudramurthy, Vinod Kumar, Kulbhushan Tikoo and Rahul Jain

Molecules 2023, 28(1), 87; https://doi.org/10.3390/molecules28010087 - 22 Dec 2022

Cited by 5 | Viewed by 2142

Abstract

Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short [...] Read more.

Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short cationic peptides exhibiting anticryptococcal activity via membrane lysis. The N-1 position of histidine was benzylated, followed by iodination at the C-5 position via electrophilic iodination, and the dipeptides were obtained after coupling with tryptophan. In vitro analysis revealed that peptides Trp-His[1-(3,5-di-tert-butylbenzyl)-5-iodo]-OMe (10d, IC₅₀ = 2.20 μg/mL; MIC = 4.01 μg/mL) and Trp-His[1-(2-iodophenyl)-5-iodo)]-OMe (10o, IC₅₀ = 2.52 μg/mL; MIC = 4.59 μg/mL) exhibit promising antifungal activities against C. neoformans. When administered in combination with standard drug amphotericin B (Amp B), a significant synergism was observed, with 4- to 16-fold increase in the potencies of both peptides and Amp B. Electron microscopy analysis with SEM and TEM showed that the dipeptides primarily act via membrane disruption, leading to pore formation and causing cell lysis. After entering the cells, the peptides interact with the intracellular components as demonstrated by confocal laser scanning microscopy (CLSM). Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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24 pages, 3695 KiB

Open AccessArticle

Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

by Mariangela Agamennone, Marialuigia Fantacuzzi, Simone Carradori, Anél Petzer, Jacobus P. Petzer, Andrea Angeli, Claudiu T. Supuran and Grazia Luisi

Molecules 2022, 27(22), 7884; https://doi.org/10.3390/molecules27227884 - 15 Nov 2022

Cited by 10 | Viewed by 2073

Abstract

The involvement of human carbonic anhydrase (hCA) IX/XII in the pathogenesis and progression of many types of cancer is well acknowledged, and more recently human monoamine oxidases (hMAOs) A and B have been found important contributors to tumor development and aggressiveness. With a [...] Read more.

The involvement of human carbonic anhydrase (hCA) IX/XII in the pathogenesis and progression of many types of cancer is well acknowledged, and more recently human monoamine oxidases (hMAOs) A and B have been found important contributors to tumor development and aggressiveness. With a view of an enzymatic dual-blockade approach, in this investigation, new coumarin-based amino acyl and (pseudo)-dipeptidyl derivatives were synthesized and firstly evaluated in vitro for inhibitory activity and selectivity against membrane-bound and cytosolic hCAs (hCA IX/XII over hCA I/II), as well as the hMAOs, to estimate their potential as anticancer agents. De novo design of peptide-coumarin conjugates was subsequently carried out and involved the combination of the widely explored coumarin nucleus with the unique biophysical and structural properties of native or modified peptides. All compounds displayed nanomolar inhibitory activities towards membrane-anchored hCAs, whilst they were unable to block the ubiquitous CA I and II isoforms. Structural features pertinent to potent and selective CA inhibitory activity are discussed, and modeling studies were found to support the biological data. Lower potency inhibition of the hMAOs was observed, with most compounds showing preferential inhibition of hMAO-A. The binding of the most potent ligands (6 and 16) to the hydrophobic active site of hMAO-A was investigated in an attempt to explain selectivity on the molecular level. Calculated Ligand Efficiency values indicate that compound 6 has the potential to serve as a lead compound for developing innovative anticancer agents based on the dual inhibition strategy. This information may help design new coumarin-based peptide molecules with diverse bioactivities. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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25 pages, 4916 KiB

Open AccessArticle

Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2

by Reda G. Yousef, Wagdy M. Eldehna, Alaa Elwan, Abdelaziz S. Abdelaziz, Ahmed B. M. Mehany, Ibraheem M. M. Gobaara, Bshra A. Alsfouk, Eslam B. Elkaeed, Ahmed M. Metwaly and Ibrahim H. Eissa

Molecules 2022, 27(13), 4079; https://doi.org/10.3390/molecules27134079 - 24 Jun 2022

Cited by 15 | Viewed by 3245

Abstract

VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be [...] Read more.

VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, ¹H-NMR, and ¹³C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC₅₀ values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC₅₀ value of 77.02 nM (compare to sorafenib: IC₅₀ = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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25 pages, 8474 KiB

Open AccessArticle

Ligand and Structure-Based In Silico Determination of the Most Promising SARS-CoV-2 nsp16-nsp10 2′-o-Methyltransferase Complex Inhibitors among 3009 FDA Approved Drugs

by Ibrahim H. Eissa, Mohamed S. Alesawy, Abdulrahman M. Saleh, Eslam B. Elkaeed, Bshra A. Alsfouk, Abdul-Aziz M. M. El-Attar and Ahmed M. Metwaly

Molecules 2022, 27(7), 2287; https://doi.org/10.3390/molecules27072287 - 31 Mar 2022

Cited by 42 | Viewed by 3429

Abstract

As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (2′OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (PDB [...] Read more.

As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (2′OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with SAM (S-Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2′OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, (1187), Calcium folinate (1913), Raltegravir (1995), Regadenoson (2176), Ertapenem (2396), Methylergometrine (2532), and Thiamine pyrophosphate hydrochloride (2612)). Out of the docked ligands, Ertapenem (2396) showed an ideal binding mode like that of the co-crystallized ligand (SAM). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, R_g, SASA, and H-bonding) have been conducted for the 2′OMTase—Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2′OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of −43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2′OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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17 pages, 2046 KiB

Open AccessArticle

Rhodamine 101 Conjugates of Triterpenoic Amides Are of Comparable Cytotoxicity as Their Rhodamine B Analogs

by Niels V. Heise, Daniel Major, Sophie Hoenke, Marie Kozubek, Immo Serbian and René Csuk

Molecules 2022, 27(7), 2220; https://doi.org/10.3390/molecules27072220 - 29 Mar 2022

Cited by 16 | Viewed by 2815

Abstract

Pentacyclic triterpenoic acids (betulinic, oleanolic, ursolic, and platanic acid) were selected and subjected to acetylation followed by the formation of amides derived from either piperazine or homopiperazine. These amides were coupled with either rhodamine B or rhodamine 101. All of these compounds were [...] Read more.

Pentacyclic triterpenoic acids (betulinic, oleanolic, ursolic, and platanic acid) were selected and subjected to acetylation followed by the formation of amides derived from either piperazine or homopiperazine. These amides were coupled with either rhodamine B or rhodamine 101. All of these compounds were screened for their cytotoxic activity in SRB assays. As a result, the cytotoxicity of the parent acids was low but increased slightly upon their acetylation while a significant increase in cytotoxicity was observed for piperazinyl and homopiperazinyl amides. A tremendous improvement in cytotoxicity was observed; however, for the rhodamine B and rhodamine 101 conjugates, and compound 27, an ursolic acid derived homopiperazinyl amide holding a rhodamine 101 residue showed an EC₅₀ = 0.05 µM for A2780 ovarian cancer cells while being less cytotoxic for non-malignant fibroblasts. To date, the rhodamine 101 derivatives presented here are the first examples of triterpene derivatives holding a rhodamine residue different from rhodamine B. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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11 pages, 3295 KiB

Open AccessArticle

Virtual Screening, Synthesis and Biological Evaluation of Streptococcus mutans Mediated Biofilm Inhibitors

by Lubna Atta, Ruqaiya Khalil, Khalid Mohammed Khan, Moatter Zehra, Faiza Saleem, Mohammad Nur-e-Alam and Zaheer Ul-Haq

Molecules 2022, 27(4), 1455; https://doi.org/10.3390/molecules27041455 - 21 Feb 2022

Cited by 5 | Viewed by 3756

Abstract

Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in [...] Read more.

Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in cases of chronic dental caries, inhibiting bacterial biofilm assembly should prevent demineralization of tooth enamel, thereby preventing tooth decay. A high throughput screening was performed in the present study to identify small molecule inhibitors of S. mutans glycosyltransferases. Multiple pharmacophore models were developed, validated with multiple datasets, and used for virtual screening against large chemical databases. Over 3000 drug-like hits were obtained that were analyzed to explore their binding mode. Finally, six compounds that showed good binding affinities were further analyzed for ADME (absorption, distribution, metabolism, and excretion) properties. The obtained in silico hits were evaluated for in vitro biofilm formation. The compounds displayed excellent antibiofilm activities with minimum inhibitory concentration (MIC) values of 15.26–250 µg/mL. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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14 pages, 2778 KiB

Open AccessArticle

Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

by Kashif Rafiq, Najeeb Ur Rehman, Sobia Ahsan Halim, Majid Khan, Ajmal Khan and Ahmed Al-Harrasi

Molecules 2022, 27(3), 816; https://doi.org/10.3390/molecules27030816 - 26 Jan 2022

Cited by 4 | Viewed by 3629

Abstract

Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we [...] Read more.

Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a–l), characterized by ¹H- and ¹³C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a–l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC₅₀ value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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12 pages, 2623 KiB

Open AccessArticle

Approach for the Design of Covalent Protein Kinase Inhibitors via Focused Deep Generative Modeling

by Atsushi Yoshimori, Filip Miljković and Jürgen Bajorath

Molecules 2022, 27(2), 570; https://doi.org/10.3390/molecules27020570 - 17 Jan 2022

Cited by 12 | Viewed by 5026

Abstract

Deep machine learning is expanding the conceptual framework and capacity of computational compound design, enabling new applications through generative modeling. We have explored the systematic design of covalent protein kinase inhibitors by learning from kinome-relevant chemical space, followed by focusing on an exemplary [...] Read more.

Deep machine learning is expanding the conceptual framework and capacity of computational compound design, enabling new applications through generative modeling. We have explored the systematic design of covalent protein kinase inhibitors by learning from kinome-relevant chemical space, followed by focusing on an exemplary kinase of interest. Covalent inhibitors experience a renaissance in drug discovery, especially for targeting protein kinases. However, computational design of this class of inhibitors has thus far only been little investigated. To this end, we have devised a computational approach combining fragment-based design and deep generative modeling augmented by three-dimensional pharmacophore screening. This approach is thought to be particularly relevant for medicinal chemistry applications because it combines knowledge-based elements with deep learning and is chemically intuitive. As an exemplary application, we report for Bruton’s tyrosine kinase (BTK), a major drug target for the treatment of inflammatory diseases and leukemia, the generation of novel candidate inhibitors with a specific chemically reactive group for covalent modification, requiring only little target-specific compound information to guide the design efforts. Newly generated compounds include known inhibitors and characteristic substructures and many novel candidates, thus lending credence to the computational approach, which is readily applicable to other targets. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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15 pages, 3286 KiB

Open AccessArticle

Development of Sustained Release Baricitinib Loaded Lipid-Polymer Hybrid Nanoparticles with Improved Oral Bioavailability

by Md. Khalid Anwer, Essam A. Ali, Muzaffar Iqbal, Mohammed Muqtader Ahmed, Mohammed F. Aldawsari, Ahmed Al Saqr, Mohd Nazam Ansari and M. Ali Aboudzadeh

Molecules 2022, 27(1), 168; https://doi.org/10.3390/molecules27010168 - 28 Dec 2021

Cited by 33 | Viewed by 4180

Abstract

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid [...] Read more.

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (−36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer–Peppas kinetic model (R² = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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16 pages, 3451 KiB

Open AccessArticle

Structural Bases for Hesperetin Derivatives: Inhibition of Protein Tyrosine Phosphatase 1B, Kinetics Mechanism and Molecular Docking Study

by Md Yousof Ali, Susoma Jannat, Hyun-Ah Jung and Jae-Sue Choi

Molecules 2021, 26(24), 7433; https://doi.org/10.3390/molecules26247433 - 8 Dec 2021

Cited by 16 | Viewed by 3518

Abstract

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5- [...] Read more.

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC₅₀ value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC₅₀ = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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14 pages, 2762 KiB

Open AccessArticle

Fabrication and Biological Assessment of Antidiabetic α-Mangostin Loaded Nanosponges: In Vitro, In Vivo, and In Silico Studies

by Faisal Usman, Hamid Saeed Shah, Sumera Zaib, Sirikhwan Manee, Jahanzeb Mudassir, Ajmal Khan, Gaber El-Saber Batiha, Khamael M. Abualnaja, Dalal Alhashmialameer and Imtiaz Khan

Molecules 2021, 26(21), 6633; https://doi.org/10.3390/molecules26216633 - 1 Nov 2021

Cited by 14 | Viewed by 4087

Abstract

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this [...] Read more.

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic β-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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23 pages, 4935 KiB

Open AccessArticle

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

by Sumera Zaib, Rubina Munir, Muhammad Tayyab Younas, Naghmana Kausar, Aliya Ibrar, Sehar Aqsa, Noorma Shahid, Tahira Tasneem Asif, Hashem O. Alsaab and Imtiaz Khan

Molecules 2021, 26(21), 6573; https://doi.org/10.3390/molecules26216573 - 30 Oct 2021

Cited by 33 | Viewed by 4133

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, ¹H- and ¹³C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC₅₀ value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC₅₀ = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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8 pages, 3328 KiB

Open AccessArticle

Evaluation of the Inhibitory Effects of Pyridylpyrazole Derivatives on LPS-Induced PGE₂ Productions and Nitric Oxide in Murine RAW 264.7 Macrophages

by Mahmoud M. Gamal El-Din, Mohammed I. El-Gamal, Young-Do Kwon, Su-Yeon Kim, Hee-Soo Han, Sang-Eun Park, Chang-Hyun Oh, Kyung-Tae Lee and Hee-Kwon Kim

Molecules 2021, 26(21), 6489; https://doi.org/10.3390/molecules26216489 - 27 Oct 2021

Cited by 1 | Viewed by 2095

Abstract

A series of thirteen triarylpyrazole analogs were investigated as inhibitors of lipopolysaccharide (LPS)-induced prostaglandin E₂ (PGE₂) and nitric oxide (NO) production in RAW 264.7 macrophages. The target compounds 1a–m have first been assessed for cytotoxicity against RAW 264.7 [...] Read more.

A series of thirteen triarylpyrazole analogs were investigated as inhibitors of lipopolysaccharide (LPS)-induced prostaglandin E₂ (PGE₂) and nitric oxide (NO) production in RAW 264.7 macrophages. The target compounds 1a–m have first been assessed for cytotoxicity against RAW 264.7 macrophages to determine their non-cytotoxic concentration(s) for anti-inflammatory testing to make sure that the inhibition of PGE₂ and NO production would not be caused by cytotoxicity. It was found that compounds 1f and 1m were the most potent PGE₂ inhibitors with IC₅₀ values of 7.1 and 1.1 μM, respectively. In addition, these compounds also showed inhibitory effects of 11.6% and 37.19% on LPS-induced NO production, respectively. The western blots analysis of COX-2 and iNOS showed that the PGE₂ and NO inhibitory effect of compound 1m are attributed to inhibition of COX-2 and iNOS protein expression through inactivation of p38. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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20 pages, 15502 KiB

Open AccessArticle

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

by Abdullah Mohammed Al-Majid, M. Ali, Mohammad Shahidul Islam, Saeed Alshahrani, Abdullah Saleh Alamary, Sammer Yousuf, M. Iqbal Choudhary and Assem Barakat

Molecules 2021, 26(20), 6305; https://doi.org/10.3390/molecules26206305 - 19 Oct 2021

Cited by 24 | Viewed by 3194

Abstract

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, [...] Read more.

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC₅₀ = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC₅₀ = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO₂ substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC₅₀ = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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85 pages, 448309 KiB

Open AccessReview

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

by Mohammed I. El-Gamal, Seyed-Omar Zaraei, Moustafa M. Madkour and Hanan S. Anbar

Molecules 2022, 27(1), 330; https://doi.org/10.3390/molecules27010330 - 5 Jan 2022

Cited by 34 | Viewed by 7145

Abstract

Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based [...] Read more.

Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011–2020). Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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31 pages, 6647 KiB

Open AccessReview

A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors

by Mohammed I. El-Gamal, Nada H. Mewafi, Nada E. Abdelmotteleb, Minnatullah A. Emara, Hamadeh Tarazi, Rawan M. Sbenati, Moustafa M. Madkour, Seyed-Omar Zaraei, Afnan I. Shahin and Hanan S. Anbar

Molecules 2021, 26(23), 7376; https://doi.org/10.3390/molecules26237376 - 5 Dec 2021

Cited by 42 | Viewed by 5929

Abstract

HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed [...] Read more.

HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppressor function. Mostly, overexpression of HER4 kinase results in cancer development. In the present article, we reviewed the structure, location, ligands, physiological functions of HER4, and its relationship to different cancer types. HER4 inhibitors reported mainly from 2016 to the present were reviewed as well. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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24 pages, 4660 KiB

Open AccessReview

Phytochemistry, Ethnopharmacological Uses, Biological Activities, and Therapeutic Applications of Cassia obtusifolia L.: A Comprehensive Review

by Md Yousof Ali, Seongkyu Park and Munseog Chang

Molecules 2021, 26(20), 6252; https://doi.org/10.3390/molecules26206252 - 15 Oct 2021

Cited by 29 | Viewed by 4800

Abstract

Cassia obtusifolia L., of the Leguminosae family, is used as a diuretic, laxative, tonic, purgative, and natural remedy for treating headache, dizziness, constipation, tophobia, and lacrimation and for improving eyesight. It is commonly used in tea in Korea. Various anthraquinone derivatives make up [...] Read more.

Cassia obtusifolia L., of the Leguminosae family, is used as a diuretic, laxative, tonic, purgative, and natural remedy for treating headache, dizziness, constipation, tophobia, and lacrimation and for improving eyesight. It is commonly used in tea in Korea. Various anthraquinone derivatives make up its main chemical constituents: emodin, chrysophanol, physcion, obtusifolin, obtusin, au rantio-obtusin, chryso-obtusin, alaternin, questin, aloe-emodin, gluco-aurantio-obtusin, gluco-obtusifolin, naphthopyrone glycosides, toralactone-9-β-gentiobioside, toralactone gentiobioside, and cassiaside. C. obtusifolia L. possesses a wide range of pharmacological properties (e.g., antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and neuroprotective properties) and may be used to treat Alzheimer’s disease, Parkinson’s disease, and cancer. In addition, C. obtusifolia L. contributes to histamine release and antiplatelet aggregation. This review summarizes the botanical, phytochemical, and pharmacological features of C. obtusifolia and its therapeutic uses. Full article

(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

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