Journal Description
Pharmaceuticals
Pharmaceuticals
is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is partners of Pharmaceuticals and their members receive a discount on the article processing charge.
- Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Pharmacology & Pharmacy) / CiteScore - Q2 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 15.6 days after submission; acceptance to publication is undertaken in 3.7 days (median values for papers published in this journal in the second half of 2022).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Testimonials: See what our editors and authors say about Pharmaceuticals.
- International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
- Companion journals for Pharmaceuticals include: Pharmacoepidemiology, Psychoactives and Drugs and Drug Candidates.
Impact Factor:
5.215 (2021);
5-Year Impact Factor:
5.711 (2021)
Latest Articles
Mast Cells as a Potential Target of Molecular Hydrogen in Regulating the Local Tissue Microenvironment
Pharmaceuticals 2023, 16(6), 817; https://doi.org/10.3390/ph16060817 (registering DOI) - 30 May 2023
Abstract
Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly advancing, giving a reason for the optimism in several healthcare practitioners regarding the management of multiple diseases, including socially significant ones (malignant neoplasms, diabetes mellitus, viral hepatitis, mental
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Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly advancing, giving a reason for the optimism in several healthcare practitioners regarding the management of multiple diseases, including socially significant ones (malignant neoplasms, diabetes mellitus, viral hepatitis, mental and behavioral disorders). However, mechanisms underlying the biological effects of H2 are still being actively debated. In this review, we focus on mast cells as a potential target for H2 at the specific tissue microenvironment level. H2 regulates the processing of pro-inflammatory components of the mast cell secretome and their entry into the extracellular matrix; this can significantly affect the capacity of the integrated-buffer metabolism and the structure of the immune landscape of the local tissue microenvironment. The analysis performed highlights several potential mechanisms for developing the biological effects of H2 and offers great opportunities for translating the obtained findings into clinical practice.
Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
Open AccessArticle
Transient Coatings from Nanoparticles Achieving Broad-Spectrum and High Antimicrobial Performance
by
, , , and
Pharmaceuticals 2023, 16(6), 816; https://doi.org/10.3390/ph16060816 (registering DOI) - 30 May 2023
Abstract
Cationic and hydrophilic coatings based on casting and drying water dispersions of two different nanoparticles (NPs) onto glass are here described and evaluated for antimicrobial activity. Discoid cationic bilayer fragments (BF) surrounded by carboxy-methylcellulose (CMC) and poly (diallyl dimethyl ammonium) chloride (PDDA) NPs
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Cationic and hydrophilic coatings based on casting and drying water dispersions of two different nanoparticles (NPs) onto glass are here described and evaluated for antimicrobial activity. Discoid cationic bilayer fragments (BF) surrounded by carboxy-methylcellulose (CMC) and poly (diallyl dimethyl ammonium) chloride (PDDA) NPs and spherical gramicidin D (Gr) NPs dispersed in water solution were cast onto glass coverslips and dried, forming a coating quantitatively evaluated against Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. From plating and colony forming units (CFU) counting, all strains interacting for 1 h with the coatings lost viability from 105 to 106, to zero CFU, at two sets of Gr and PDDA doses: 4.6 and 25 μg, respectively, or, 0.94 and 5 μg, respectively. Combinations produced broad spectrum, antimicrobial coatings; PDDA electrostatically attached to the microbes damaging cell walls, allowing Gr NPs interaction with the cell membrane. This concerted action promoted optimal activity at low Gr and PDDA doses. Further washing and drying of the deposited dried coatings showed that they were washed out so that antimicrobial activity was no longer present on the glass surface. Significant applications in biomedical materials can be foreseen for these transient coatings.
Full article
(This article belongs to the Special Issue Self-Assembled Nanoparticles: An Emerging Delivery Platform for Drugs)
Open AccessArticle
Monitoring of Levosimendan Administration in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery and Effect of Two Different Dosing Schemes on Hemodynamic and Echocardiographic Parameters
by
, , , , , , , , and
Pharmaceuticals 2023, 16(6), 815; https://doi.org/10.3390/ph16060815 (registering DOI) - 30 May 2023
Abstract
Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might
[...] Read more.
Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. Materials and Methods: In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 μg/kg or 12 μg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. Results: A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1–50 ng/mL for LS and 1–50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 μg/kg. Additionally, administration of LS at a dose of 12 μg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. Conclusion: LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery.
Full article
(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)
Open AccessArticle
Selenylated Imidazo [1,2-a]pyridine Induces Apoptosis and Oxidative Stress in 2D and 3D Models of Colon Cancer Cells
by
, , , , , , , and
Pharmaceuticals 2023, 16(6), 814; https://doi.org/10.3390/ph16060814 (registering DOI) - 30 May 2023
Abstract
Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor
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Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor cells. This study aimed to investigate the cytotoxic effect of MRK-107, an imidazo [1,2- a]pyridine derivative, in 2D and 3D cell culture models of colon cancer (Caco-2 and HT-29). Sulforhodamine B results revealed a GI50 of 2.4 µM for Caco-2, 1.1 µM for HT-29, and 22.19 µM for NIH/3T3 in 2D cultures after 48 h of treatment. Cell recovery, migration, clonogenic, and Ki-67 results corroborated that MRK-107 inhibits cell proliferation and prevents cell regeneration and metastatic transition by selectively reducing migratory and clonogenic capacity; non-tumor cells (NIH/3T3) re-established proliferation in less than 18 h. The oxidative stress markers DCFH-DA and TBARS revealed increased ROS generation and oxidative damage. Caspases-3/7 are activated and induce apoptosis as the main mode of cell death in both cell models, as assessed by annexin V-FITC and acridine orange/ethidium bromide staining. MRK-107 is a selective, redox-active compound with pro-oxidant and pro-apoptotic properties and the capacity to activate antiproliferative pathways, showing promise in anticancer drug research.
Full article
(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)
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Open AccessReview
Extra-Gonadal and Non-Canonical Effects of FSH in Males
by
, , , , , , , , , , , and
Pharmaceuticals 2023, 16(6), 813; https://doi.org/10.3390/ph16060813 (registering DOI) - 30 May 2023
Abstract
Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which
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Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.
Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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Open AccessArticle
NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder
Pharmaceuticals 2023, 16(6), 812; https://doi.org/10.3390/ph16060812 (registering DOI) - 30 May 2023
Abstract
Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of
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Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague–Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder.
Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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Spasmolytic and Uroprotective Effects of Apigenin by Downregulation of TGF-β and iNOS Pathways and Upregulation of Antioxidant Mechanisms: In Vitro and In Silico Analysis
by
, , , , , , and
Pharmaceuticals 2023, 16(6), 811; https://doi.org/10.3390/ph16060811 (registering DOI) - 30 May 2023
Abstract
Apigenin is a phytochemical obtained from Chamomilla recutita. Its role in interstitial cystitis is not yet known. The present study is aimed at understanding the uroprotective and spasmolytic effects of apigenin in cyclophosphamide-induced interstitial cystitis. The uroprotective role of apigenin was analyzed by
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Apigenin is a phytochemical obtained from Chamomilla recutita. Its role in interstitial cystitis is not yet known. The present study is aimed at understanding the uroprotective and spasmolytic effects of apigenin in cyclophosphamide-induced interstitial cystitis. The uroprotective role of apigenin was analyzed by qRT-PCR, macroscopic analysis, Evans blue dye leakage, histological evaluation, and molecular docking. The spasmolytic response was measured by adding cumulative concentrations of apigenin to isolated bladder tissue pre-contracted with KCl (80 mM) and carbachol (10−9–10−4) on non-incubated and pre-incubated tissues with atropine, 4DAMP, methoctramine, glibenclamide, barium chloride, nifedipine, indomethacin, and propranolol. Apigenin inhibited pro-inflammatory cytokines (IL-6, TNF-α and TGF 1-β) and oxidant enzymes (iNOS) while increasing antioxidant enzymes (SOD, CAT, and GSH) in CYP-treated groups compared to the control. Apigenin restored normal tissue of the bladder by decreasing pain, edema, and hemorrhage. Molecular docking further confirmed the antioxidant and anti-inflammatory properties of apigenin. Apigenin produced relaxation against carbachol-mediated contractions, probably via blockade of M3 receptors, KATP channels, L-type calcium channels, and prostaglandin inhibition. While the blockade of M2 receptors, KIR channels, and β-adrenergic receptors did not contribute to an apigenin-induced spasmolytic effect, apigenin presented as a possible spasmolytic and uroprotective agent with anti-inflammatory, antioxidant effects by attenuating TGF-β/iNOS-related tissue damage and bladder muscle overactivity. Thus, it is a potential agent likely to be used in treatment of interstitial cystitis.
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(This article belongs to the Section Natural Products)
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Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives
by
and
Pharmaceuticals 2023, 16(6), 810; https://doi.org/10.3390/ph16060810 (registering DOI) - 30 May 2023
Abstract
Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry
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Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous systems (CNS). Consequently, clinical translation of peptide/protein therapeutics for the treatment of CNS diseases has been limited. Over the past decades, developing effective delivery strategies for peptides and proteins has gained extensive attention, in particular with localized delivery strategies, due to the fact that they are capable of circumventing the physiological barrier to directly introduce macromolecular therapeutics into the CNS to improve therapeutic effects and reduce systemic side effects. Here, we discuss various local administration and formulation strategies that have shown successes in the treatment of CNS diseases using peptide/protein therapeutics. Lastly, we discuss challenges and future perspectives of these approaches.
Full article
(This article belongs to the Special Issue Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives)
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Open AccessArticle
Evaluation of the Anticancer Activity of Calcium Ions Introduced into Human Breast Adenocarcinoma Cells MCF-7/WT and MCF-7/DOX by Electroporation
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, , , , and
Pharmaceuticals 2023, 16(6), 809; https://doi.org/10.3390/ph16060809 - 30 May 2023
Abstract
Breast cancer ranks among the top three most common malignant neoplasms in Poland. The use of calcium ion-assisted electroporation is an alternative approach to the classic treatment of this disease. The studies conducted in recent years confirm the effectiveness of electroporation with calcium
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Breast cancer ranks among the top three most common malignant neoplasms in Poland. The use of calcium ion-assisted electroporation is an alternative approach to the classic treatment of this disease. The studies conducted in recent years confirm the effectiveness of electroporation with calcium ions. Electroporation is a method that uses short electrical pulses to create transitional pores in the cell membrane to allow the penetration of certain drugs. The aim of this study was to investigate the antitumor effects of electroporation alone and calcium ion-assisted electroporation on human mammary adenocarcinoma cells that are sensitive (MCF-7/WT) and resistant to doxorubicin (MCF-7/DOX). The cell viability was assessed using independent tests: MTT and SRB. The type of cell death after the applied therapy was determined by TUNEL and flow cytometry (FACS) methods. The expression of Cav3.1 and Cav3.2 proteins of T-type voltage-gated calcium channels was assessed by immunocytochemistry, and changes in the morphology of CaEP-treated cells were visualized using a holotomographic microscope. The obtained results confirmed the effectiveness of the investigated therapeutic method. The results of the work constitute a good basis for planning research at the in vivo level and in the future to develop a more effective and safer method of breast cancer treatment for patients.
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(This article belongs to the Special Issue Pharmaceutical Science in Electrochemotherapy)
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Unveiling the Potential of BenzylethyleneAryl–Urea Scaffolds for the Design of New Onco Immunomodulating Agents
Pharmaceuticals 2023, 16(6), 808; https://doi.org/10.3390/ph16060808 - 29 May 2023
Abstract
This work focuses on the development of thirteen benzylethylenearyl ureas and one carbamate. After the synthesis and purification of the compounds, we studied their antiproliferative action on cell lines, such as HEK-293, and cancer ones, such as HT-29, MCF-7 or A-549, on the
[...] Read more.
This work focuses on the development of thirteen benzylethylenearyl ureas and one carbamate. After the synthesis and purification of the compounds, we studied their antiproliferative action on cell lines, such as HEK-293, and cancer ones, such as HT-29, MCF-7 or A-549, on the immune Jurkat T-cells and endothelial cells HMEC-1. Compounds C.1, C.3, C.12 and C.14 were selected for further biological studies to establish their potential as immunomodulating agents. Some of the derivatives exhibited significant inhibitory effects on both targets: PD-L1 and VEGFR-2 in the HT-29 cell line, showing that urea C.12 is active against both targets. Some compounds could inhibit more than 50% of cancer cell proliferation compared to non-treated ones when assessed in co-cultures using HT-29 and THP-1 cells. In addition, they significantly reduced CD11b expression, which is a promising target for immune modulation in anticancer immunotherapies.
Full article
(This article belongs to the Special Issue Urea and Thiourea Derivatives in Modern Drug Discovery and Medicinal Chemistry)
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Therapeutic Potential of Hibiscus sabdariffa Linn. in Attenuating Cardiovascular Risk Factors
by
, , , , , , , , , , , and
Pharmaceuticals 2023, 16(6), 807; https://doi.org/10.3390/ph16060807 - 29 May 2023
Abstract
Cardiovascular diseases (CVDs) represent a broad spectrum of diseases afflicting the heart and blood vessels and remain a major cause of death and disability worldwide. CVD progression is strongly associated with risk factors, including hypertension, hyperglycemia, dyslipidemia, oxidative stress, inflammation, fibrosis, and apoptosis.
[...] Read more.
Cardiovascular diseases (CVDs) represent a broad spectrum of diseases afflicting the heart and blood vessels and remain a major cause of death and disability worldwide. CVD progression is strongly associated with risk factors, including hypertension, hyperglycemia, dyslipidemia, oxidative stress, inflammation, fibrosis, and apoptosis. These risk factors lead to oxidative damage that results in various cardiovascular complications including endothelial dysfunctions, alterations in vascular integrity, the formation of atherosclerosis, as well as incorrigible cardiac remodeling. The use of conventional pharmacological therapy is one of the current preventive measures to control the development of CVDs. However, as undesirable side effects from drug use have become a recent issue, alternative treatment from natural products is being sought in medicinal plants and is gaining interest. Roselle (Hibiscus sabdariffa Linn.) has been reported to contain various bioactive compounds that exert anti-hyperlipidemia, anti-hyperglycemia, anti-hypertension, antioxidative, anti-inflammation, and anti-fibrosis effects. These properties of roselle, especially from its calyx, have relevance to its therapeutic and cardiovascular protection effects in humans. This review summarizes the findings of recent preclinical and clinical studies on roselle as a prophylactic and therapeutic agent in attenuating cardiovascular risk factors and associated mechanisms.
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(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals 2022)
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Synthesis, Physicochemical Characterization, Biological Evaluation, In Silico and Molecular Docking Studies of Pd(II) Complexes with P, S-Donor Ligands
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, , , , , , , and
Pharmaceuticals 2023, 16(6), 806; https://doi.org/10.3390/ph16060806 - 29 May 2023
Abstract
One homoleptic (1) and three heteroleptic (2–4) palladium(II) complexes were synthesized and characterized by various physicochemical techniques, i.e., elemental analysis, FTIR, Raman spectroscopy, 1H, 13C, and 31P NMR. Compound 1 was also confirmed by
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One homoleptic (1) and three heteroleptic (2–4) palladium(II) complexes were synthesized and characterized by various physicochemical techniques, i.e., elemental analysis, FTIR, Raman spectroscopy, 1H, 13C, and 31P NMR. Compound 1 was also confirmed by single crystal XRD, showing a slightly distorted square planar geometry. The antibacterial results obtained via the agar-well diffusion method for compound 1 were maximum among the screen compounds. All the compounds have shown good to significant antibacterial results against the tested bacterial strains, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus, except 2 against Klebsiella pneumonia. Similarly, the molecular docking study of compound 3 has shown the best affinity with binding energy scores of −8.6569, −6.5716, and −7.6966 kcal/mol against Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus, respectively. Compound 2 has exhibited the highest activity (3.67 µM), followed by compound 3 (4.57 µM), 1 (6.94 µM), and 4 (21.7 µM) against the DU145 human prostate cancer cell line using the sulforhodamine B (SRB) method as compared to cisplatin (>200 µM). The highest docking score was obtained for compounds 2 (−7.5148 kcal/mol) and 3 (−7.0343 kcal/mol). Compound 2 shows that the Cl atom of the compound acts as a chain side acceptor for the DR5 receptor residue Asp B218 and the pyridine ring is involved in interaction with the Tyr A50 residue via arene-H, while Compound 3 interacts with the Asp B218 residue via the Cl atom. The physicochemical parameters determined by the SwissADME webserver revealed that no blood-brain barrier (BBB) permeation is predicted for all four compounds, while gastrointestinal absorption is low for compound 1 and high for the rest of the compounds (2–4). As concluding remarks based on the obtained in vitro biological results, the evaluated compounds after in vivo studies might be a good choice for future antibiotics and anticancer agents.
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(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)
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2-Substituted-3-(5-Substituted-1,3,4-oxadiazol/thiadiazol-2-yl) Thiazolidin-4-one Derivatives: Synthesis, Anticancer, Antimicrobial, and Antioxidant Potential
by
, , , , , , , , , , and
Pharmaceuticals 2023, 16(6), 805; https://doi.org/10.3390/ph16060805 - 29 May 2023
Abstract
In this innovative research, a novel series of thiazolidin-4-one analogues having a 1,3,4-oxadiazole/thiadiazole moiety were derived and the structures of all the newly obtained molecules were established using different physicochemical and analytical means (1H-NMR, FTIR, mass spectra, and elemental analyses). The
[...] Read more.
In this innovative research, a novel series of thiazolidin-4-one analogues having a 1,3,4-oxadiazole/thiadiazole moiety were derived and the structures of all the newly obtained molecules were established using different physicochemical and analytical means (1H-NMR, FTIR, mass spectra, and elemental analyses). The synthesized molecules were then investigated for their antiproliferative, antimicrobial, and antioxidant potential. The cytotoxicity screening studies revealed that analogues D-1, D-6, D-15, and D-16 possessed comparable efficacy, within the IC50 range (1 to 7 μM), when taking doxorubicin as a reference drug (IC50 = 0.5 μM). The antimicrobial activity was assessed using different Gram-(+) and Gram-(−) bacterial and fungal strains and the results revealed that molecules D-2, D-4, D-6, D-19, and D-20 possessed potent activity against selective strains of microbes with MIC ranges of 3.58 to 8.74 µM. The antioxidant evaluation was performed using the DPPH assay and the screening results revealed that analogue D-16 was the most potent derivative (IC50 = 22.3 µM) when compared with the positive control, ascorbic acid (IC50 = 111.6 µM). Structure–activity relationship (SAR) studies of the synthesized novel derivatives revealed that para-substituted halogen and hydroxy derivatives have remarkable potential against the MCF-7 cancer cell line and antioxidant potential. Similarly, electron-withdrawing groups (Cl/NO2) and -donating groups at the para position possess moderate to promising antimicrobial potential.
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(This article belongs to the Special Issue Pyrazole and Thiazole Derivatives in Medicinal Chemistry)
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Design, Synthesis, Biological Evaluation, and Molecular Docking Study of 4,6-Dimethyl-5-aryl/alkyl-2-[2-hydroxy-3-(4-substituted-1-piperazinyl)propyl]pyrrolo[3,4-c]pyrrole-1,3(2H,5H)-diones as Anti-Inflammatory Agents with Dual Inhibition of COX and LOX
by
, , , , and
Pharmaceuticals 2023, 16(6), 804; https://doi.org/10.3390/ph16060804 - 29 May 2023
Abstract
In the present study, we characterize the biological activity of a newly designed and synthesized series of 15 compounds 2-[2-hydroxy-3-(4-substituted-1-piperazinyl)propyl] derivatives of pyrrolo[3,4-c]pyrrole 3a–3o. The compounds were obtained with good yields of pyrrolo[3,4-c]pyrrole scaffold 2a–
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In the present study, we characterize the biological activity of a newly designed and synthesized series of 15 compounds 2-[2-hydroxy-3-(4-substituted-1-piperazinyl)propyl] derivatives of pyrrolo[3,4-c]pyrrole 3a–3o. The compounds were obtained with good yields of pyrrolo[3,4-c]pyrrole scaffold 2a–2c with secondary amines in C2H5OH. The chemical structures of the compounds were characterized by 1H-NMR, 13C-NMR, FT-IR, and MS. All the new compounds were investigated for their potencies to inhibit the activity of three enzymes, i.e., COX-1, COX-2, and LOX, by a colorimetric inhibitor screening assay. In order to analyze the structural basis of interactions between the ligands and cyclooxygenase/lipooxygenase, experimental data were supported by the results of molecular docking simulations. The data indicate that all of the tested compounds influence the activity of COX-1, COX-2, and LOX.
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(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation with Potential Anti-inflammatory Activity)
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In Silico Characterization and Analysis of Clinically Significant Variants of Lipase-H (LIPH Gene) Protein Associated with Hypotrichosis
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, , , , , , , , , , and
Pharmaceuticals 2023, 16(6), 803; https://doi.org/10.3390/ph16060803 - 29 May 2023
Abstract
Hypotrichosis is an uncommon type of alopecia (hair loss) characterized by coarse scalp hair caused by the reduced or fully terminated activity of the Lipase-H (LIPH) enzyme. LIPH gene mutations contribute to the development of irregular or non-functional proteins. Because several cellular processes,
[...] Read more.
Hypotrichosis is an uncommon type of alopecia (hair loss) characterized by coarse scalp hair caused by the reduced or fully terminated activity of the Lipase-H (LIPH) enzyme. LIPH gene mutations contribute to the development of irregular or non-functional proteins. Because several cellular processes, including cell maturation and proliferation, are inhibited when this enzyme is inactive, the hair follicles become structurally unreliable, undeveloped, and immature. This results in brittle hair, as well as altered hair shaft development and structure. Because of these nsSNPs, the protein’s structure and/or function may be altered. Given the difficulty in discovering functional SNPs in genes associated with disease, it is possible to assess potential functional SNPs before conducting broader population investigations. As a result, in our in silico analysis, we separated potentially hazardous nsSNPs of the LIPH gene from benign representatives using a variety of sequencing and architecture-based bioinformatics approaches. Using seven prediction algorithms, 9 out of a total of 215 nsSNPs were shown to be the most likely to cause harm. In order to distinguish between potentially harmful and benign nsSNPs of the LIPH gene, in our in silico investigation, we employed a range of sequence- and architecture-based bioinformatics techniques. Three nsSNPs (W108R, C246S, and H248N) were chosen as potentially harmful. The present findings will likely be helpful in future large population-based studies, as well as in drug discovery, particularly in the creation of personalized medicine, since this study provides an initial thorough investigation of the functional nsSNPs of LIPH.
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(This article belongs to the Special Issue Drug Candidates for the Treatment of Skin Diseases)
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Recent Advances in Doxorubicin Formulation to Enhance Pharmacokinetics and Tumor Targeting
Pharmaceuticals 2023, 16(6), 802; https://doi.org/10.3390/ph16060802 - 29 May 2023
Abstract
Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces
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Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanoparticles, and polymer-drug conjugates, under clinical use or trials to increase its therapeutic efficacy. To improve the bioavailability of DOX in intravenous and oral cancer treatment, studies have proposed a pH- or redox-sensitive and receptor-targeted system for overcoming DOX resistance and increasing therapeutic efficacy without causing DOX-induced toxicity. Multifunctional formulations of DOX with mucoadhesiveness and increased intestinal permeability through tight-junction modulation and P-gp inhibition have also been used as orally bioavailable DOX in the preclinical stage. The increasing trends of developing oral formulations from intravenous formulations, the application of mucoadhesive technology, permeation-enhancing technology, and pharmacokinetic modulation with functional excipients might facilitate the further development of oral DOX.
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(This article belongs to the Special Issue Feature Reviews in Pharmaceutical Technology)
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Open AccessReview
A Review of Recent Pharmacological Advances in the Management of Diabetes-Associated Peripheral Neuropathy
Pharmaceuticals 2023, 16(6), 801; https://doi.org/10.3390/ph16060801 - 29 May 2023
Abstract
Diabetic peripheral neuropathy is a common complication of longstanding diabetes mellitus. These neuropathies can present in various forms, and with the increasing prevalence of diabetes mellitus, a subsequent increase in peripheral neuropathy cases has been noted. Peripheral neuropathy has a significant societal and
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Diabetic peripheral neuropathy is a common complication of longstanding diabetes mellitus. These neuropathies can present in various forms, and with the increasing prevalence of diabetes mellitus, a subsequent increase in peripheral neuropathy cases has been noted. Peripheral neuropathy has a significant societal and economic burden, with patients requiring concomitant medication and often experiencing a decline in their quality of life. There is currently a wide variety of pharmacological interventions, including serotonin norepinephrine reuptake inhibitors, gapentanoids, sodium channel blockers, and tricyclic antidepressants. These medications will be discussed, as well as their respective efficacies. Recent advances in the treatment of diabetes mellitus with incretin system-modulating drugs, specifically glucagon-like peptide-1 agonists, have been promising, and their potential implication in the treatment of peripheral diabetic neuropathy is discussed in this review.
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(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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Ion Channels and Personalized Medicine in Gynecological Cancers
by
, , , , , , , and
Pharmaceuticals 2023, 16(6), 800; https://doi.org/10.3390/ph16060800 - 29 May 2023
Abstract
Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of
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Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of malignancies, including ovarian, cervical, and endometrial cancer. The altered expression or function of several ion channels have been associated with tumor aggressiveness, increased proliferation, migration, invasion, and metastasis of cancer cells and with poor prognosis in gynecological cancer patients. Most ion channels are integral membrane proteins easily accessible by drugs. Interestingly, a plethora of ion channel blockers have demonstrated anticancer activity. Consequently, some ion channels have been proposed as oncogenes, cancer, and prognostic biomarkers, as well as therapeutic targets in gynecological cancers. Here, we review the association of ion channels with the properties of cancer cells in these tumors, which makes them very promising candidates to be exploited in personalized medicine. The detailed analysis of the expression pattern and function of ion channels could help to improve the clinical outcomes in gynecological cancer patients.
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(This article belongs to the Special Issue Personalized Medicine in Gynecological Cancer)
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Phase II, Double-Blinded, Randomized, Placebo-Controlled Clinical Trial Investigating the Efficacy of Mebendazole in the Management of Symptomatic COVID-19 Patients
by
, , , and
Pharmaceuticals 2023, 16(6), 799; https://doi.org/10.3390/ph16060799 - 29 May 2023
Abstract
The outbreak of the COVID-19 pandemic has spread throughout the world, affecting almost all nations and territories. The current double-blind, randomized, placebo-controlled, phase II clinical trial sought to evaluate the clinical efficacy and safety of mebendazole as an adjuvant therapy for outpatients with
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The outbreak of the COVID-19 pandemic has spread throughout the world, affecting almost all nations and territories. The current double-blind, randomized, placebo-controlled, phase II clinical trial sought to evaluate the clinical efficacy and safety of mebendazole as an adjuvant therapy for outpatients with COVID-19. The patients were recruited and divided into two groups: a Mebendazole-treated group and placebo group. The mebendazole and placebo groups were matched for age, sex, and complete blood count (CBC) with differential and liver and kidney function tests at baseline. On the third day, the C-reactive protein (CRP) levels were lower (2.03 ± 1.45 vs. 5.45 ± 3.95, p < 0.001) and the cycle threshold (CT) levels were higher (27.21 ± 3.81 vs. 24.40 ± 3.09, p = 0.046) significantly in the mebendazole group than in the placebo group on the third day. Furthermore, CRP decreased and CT dramatically increased on day three compared to the baseline day in the mebendazole group (p < 0.001 and p = 0.008, respectively). There was a significant inverse correlation between lymphocytes and CT levels in the mebendazole group (r = −0.491, p = 0.039) but not in the placebo group (r = 0.051, p = 0.888). Mebendazole therapy increased innate immunity and returned inflammation to normal levels in COVID-19 outpatients faster than it did in the placebo group in this clinical trial. Our findings add to the growing body of research on the clinical and microbiological benefits of repurposing antiparasitic therapy, specifically mebendazole, for SARS-CoV-2 infection and other viral infections.
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(This article belongs to the Section Pharmacology)
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Synthesis and Preclinical Evaluation of Novel 68Ga-Labeled (R)-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging
by
, , , , , and
Pharmaceuticals 2023, 16(6), 798; https://doi.org/10.3390/ph16060798 - 28 May 2023
Abstract
Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic
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Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 (DOTA-conjugated (R)-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated ((R)-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). natGa- and 68Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported natGa/68Ga-complexed PNT6555. Enzymatic assays showed that FAP binding affinities (IC50) of natGa-SB02055, natGa-SB04028 and natGa-PNT6555 were 0.41 ± 0.06, 13.9 ± 1.29 and 78.1 ± 4.59 nM, respectively. PET imaging and biodistribution studies in HEK293T:hFAP tumor-bearing mice showed that while [68Ga]Ga-SB02055 presented with a nominal tumor uptake (1.08 ± 0.37 %ID/g), [68Ga]Ga-SB04028 demonstrated clear tumor visualization with ~1.5-fold higher tumor uptake (10.1 ± 0.42 %ID/g) compared to [68Ga]Ga-PNT6555 (6.38 ± 0.45 %ID/g). High accumulation in the bladder indicated renal excretion of all three tracers. [68Ga]Ga-SB04028 displayed a low background level uptake in most normal organs, and comparable to [68Ga]Ga-PNT6555. However, since its tumor uptake was considerably higher than [68Ga]Ga-PNT6555, the corresponding tumor-to-organ uptake ratios for [68Ga]Ga-SB04028 were also significantly greater than [68Ga]Ga-PNT6555. Our data demonstrate that (R)-(((quinoline-4-carbonyl)-d-alanyl)pyrrolidin-2-yl)boronic acid is a promising pharmacophore for the design of FAP-targeted radiopharmaceuticals for cancer imaging and radioligand therapy.
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(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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