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Special Issue "The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry"

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 20 December 2023 | Viewed by 3519

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Special Issue Editor

Prof. Dr. Mary J. Meegan

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Guest Editor

Trinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152−160 Pearse Street, Dublin 2 D02 R590, Ireland
Interests: anticancer drug design; breast cancer; novel antioestrogens; tubulin targeting agents; azetidinones; antioestrogen–drug conjugates; oestrogen receptor; Burkitt's lymphoma; chronic lymphocytic leukaemia
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Special Issue Information

Dear Colleagues,

As a multidisciplinary research subject, medicinal chemistry involves topics within biology, medicine, chemistry, and covers therapeutic fields, ranging from anticancer, antiviral and antimicrobial agents to molecules potentially active in endocrine, inflammation, neurological, cardiovascular and autoimmune diseases. The numerous advances in this field, ranging from theoretical design and in silico screening to synthetic and analytical methodologies , lead discovery and optimization methods, structure-based drug design and bioinformatics are contributing to more efficient and sophisticated strategies to access therapeutic potential.

This Special Issue aims to discuss new knowledge and new cutting-edge developments related to all aspects of medicinal chemistry, which will contribute to our understanding of the relationship between molecular structure and biological activity or the mode of action of drugs. Authors are invited to contribute original research papers or reviews that report on the discovery, design, synthesis, identification and metabolism of biologically active compounds and drug candidates, together with structure–activity relationships and studies that describe investigations of the mechanism of action at the molecular level of these novel biologically active compounds.

Prof. Dr. Mary J. Meegan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

drug discovery
novel drug targets
drug discovery
drug design and development
synthetic methods for drugs
analytical methodologies
in silico screening
structure and ligand-based drug design
structure–activity relationships (SAR)
drug metabolism

Published Papers (6 papers)

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Research

27 pages, 11971 KiB

Open AccessArticle

Novel Anthranilic Acid Hybrids—An Alternative Weapon against Inflammatory Diseases

Mehran Feizi-Dehnayebi

and

Pharmaceuticals 2023, 16(12), 1660; https://doi.org/10.3390/ph16121660 - 29 Nov 2023

Viewed by 319

Abstract

Anti-inflammatory drugs are used to relieve pain, fever, and inflammation while protecting the cardiovascular system. However, the side effects of currently available medications have limited their usage. Due to these adverse effects, there is a significant need for new drugs. The current trend of research has shifted towards the synthesis of novel anthranilic acid hybrids as anti-inflammatory agents. Phenyl- or benzyl-substituted hybrids exerted very good anti-inflammatory effects in preventing albumin denaturation. To confirm their anti-inflammatory effects, additional ex vivo tests were conducted. These immunohistochemical studies explicated the same compounds with better anti-inflammatory potential. To determine the binding affinity and interaction mode, as well as to explain the anti-inflammatory activities, the molecular docking simulation of the compounds was investigated against human serum albumin. The biological evaluation of the compounds was completed, assessing their antimicrobial activity and spasmolytic effect. Based on the experimental data, we can conclude that a collection of novel hybrids was successfully synthesized, and they can be considered anti-inflammatory drug candidates—alternatives to current therapeutics. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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27 pages, 6218 KiB

Open AccessArticle

Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach

Cleydson B. R. Santos

and

Franco H. A. Leite

Pharmaceuticals 2023, 16(12), 1657; https://doi.org/10.3390/ph16121657 - 28 Nov 2023

Viewed by 258

Abstract

Alzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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24 pages, 3428 KiB

Open AccessArticle

Hierarchical Virtual Screening of Potential New Antibiotics from Polyoxygenated Dibenzofurans against Staphylococcus aureus Strains

Gabriela S. Rodrigues

Aldo A. Proietti-Junior

Gabriela B. dos Santos

Joaquín M. Campos

and

Cleydson B. R. Santos

Pharmaceuticals 2023, 16(10), 1430; https://doi.org/10.3390/ph16101430 - 09 Oct 2023

Viewed by 667

Abstract

Staphylococcus aureus is a microorganism with high morbidity and mortality due to antibiotic-resistant strains, making the search for new therapeutic options urgent. In this context, computational drug design can facilitate the drug discovery process, optimizing time and resources. In this work, computational methods involving ligand- and structure-based virtual screening were employed to identify potential antibacterial agents against the S. aureus MRSA and VRSA strains. To achieve this goal, tetrahydroxybenzofuran, a promising antibacterial agent according to in vitro tests described in the literature, was adopted as the pivotal molecule and derivative molecules were considered to generate a pharmacophore model, which was used to perform virtual screening on the Pharmit platform. Through this result, twenty-four molecules were selected from the MolPort^® database. Using the Tanimoto Index on the BindingDB web server, it was possible to select eighteen molecules with greater structural similarity in relation to commercial antibiotics (methicillin and oxacillin). Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the eighteen most similar molecules, showed that only three exhibited desired properties (LB255, LB320 and LB415). In the molecular docking study, the promising molecules LB255, LB320 and LB415 showed significant values in both molecular targets. LB320 presented better binding affinity to MRSA (−8.18 kcal/mol) and VRSA (−8.01 kcal/mol) targets. Through PASS web server, the three molecules, specially LB320, showed potential for antibacterial activity. Synthetic accessibility (SA) analysis performed on AMBIT and SwissADME web servers showed that LB255 and LB415 can be considered difficult to synthesize and LB320 is considered easy. In conclusion, the results suggest that these ligands, particularly LB320, may bind strongly to the studied targets and may have appropriate ADME/Tox properties in experimental studies. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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19 pages, 3399 KiB

Open AccessArticle

Anti-Inflammatory Activity of N′-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide Derivative via sGC-NO/Cytokine Pathway

Pablo Rayff da Silva

Nadjaele de Melo Apolinário

Simone Ângela Soares da Silva

Maria Elaine Cristina Araruna

Thássia Borges Costa

Yvnni M. S. de Medeiros e Silva

Teresinha Gonçalves da Silva

Ricardo Olímpio de Moura

and

Vanda Lucia dos Santos

Pharmaceuticals 2023, 16(10), 1415; https://doi.org/10.3390/ph16101415 - 05 Oct 2023

Viewed by 550

Abstract

The N-acylhydrazone function has been reported as a pharmacophore group of molecules with diverse pharmacological activities, including anti-inflammatory effects. Therefore, this study was designed to evaluate the anti-inflammatory potential of the compound N′-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide (JR19) in vivo. The study started with the carrageenan-induced peritonitis model, followed by an investigation of leukocyte migration using the subcutaneous air pouch test and an assessment of the antinociceptive profile using formalin-induced pain. A preliminary molecular docking study focusing on the crystallographic structures of NFκB, iNOS, and sGC was performed to determine the likely mechanism of action. The computational study revealed satisfactory interaction energies with the selected targets, and the same peritonitis model was used to validate the involvement of the nitric oxide pathway and cytokine expression in the peritoneal exudate of mice pretreated with L-NAME or methylene blue. In the peritonitis assay, JR19 (10 and 20 mg/kg) reduced leukocyte migration by 59% and 52%, respectively, compared to the vehicle group, with the 10 mg/kg dose used in subsequent assays. In the subcutaneous air pouch assay, the reduction in cell migration was 66%, and the response to intraplantar formalin was reduced by 39%, particularly during the inflammatory phase, suggesting that the compound lacks central analgesic activity. In addition, a reversal of the anti-inflammatory effect was observed in mice pretreated with L-NAME or methylene blue, indicating the involvement of iNOS and sGC in the anti-inflammatory response of JR19. The compound effectively and significantly decreased the levels of IL-6, TNF-α, IL-17, and IFN-γ, and this effect was reversed in animals pretreated with L-NAME, supporting a NO-dependent anti-inflammatory effect. In contrast, pretreatment with methylene blue only reversed the reduction in TNF-α levels. Therefore, these results demonstrate the pharmacological potential of the novel N-acylhydrazone derivative, which acts through the nitric oxide pathway and cytokine signaling, making it a strong candidate as an anti-inflammatory and immunomodulatory agent. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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19 pages, 6089 KiB

Open AccessArticle

Nature-Inspired Compounds: Synthesis and Antibacterial Susceptibility Testing of Eugenol Derivatives against H. pylori Strains

Simone Carradori

Alessandra Ammazzalorso

and

Pharmaceuticals 2023, 16(9), 1317; https://doi.org/10.3390/ph16091317 - 18 Sep 2023

Viewed by 623

Abstract

The antimicrobial properties of one of the most important secondary metabolites, Eugenol (EU), inspired us to design and synthesize three different series of derivatives enhancing its parent compound’s anti-Helicobacter pylori activity. Thus, we prepared semisynthetic derivatives through (A) diazo aryl functionalization, (B) derivatization of the hydroxy group of EU, and (C) elongation of the allyl radical by incorporating a chalcogen atom. The antibacterial evaluation was performed on the reference NCTC 11637 strain and on three drug-resistant clinical isolates and the minimal inhibitory and bactericidal concentrations (MICs and MBCs) highlight the role of chalcogens in enhancing the antimicrobial activity (less than 4 µg/mL for some compounds) of the EU scaffold (32–64 µg/mL). Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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23 pages, 3292 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents

Lamya H. Al-Wahaibi

Anber F. Mohammed

Mostafa H. Abdelrahman

Laurent Trembleau

and

Bahaa G. M. Youssif

Pharmaceuticals 2023, 16(7), 1039; https://doi.org/10.3390/ph16071039 - 22 Jul 2023

Cited by 1 | Viewed by 698

Abstract

A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i demonstrated promising antiproliferative activity, with GI₅₀ values ranging from 26 nM to 86 nM compared to erlotinib’s 33 nM. The most potent antiproliferative derivatives—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC₅₀ value of 71 ± 06 nM, which is higher than the reference erlotinib (IC₅₀ = 80 ± 05 nM). Compounds Va, Ve, Vf, Vg, and Vh were further tested for BRAF^V600E inhibitory activity. The tested compounds inhibited BRAF^V600E with IC₅₀ values ranging from 77 nM to 107 nM compared to erlotinib’s IC₅₀ value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAF^V600E, and VEGFR-2. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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Special Issue "The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry"

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