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Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 June 2024 | Viewed by 2285

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Dr. Ivana Pibiri

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Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, University of Palermo, 90128 Palermo, Italy
Interests: synthesis of heterocyclic compounds; heterocyclic chemistry; medicinal and pharmaceutical chemistry; synthetic medicinal chemistry; natural product chemistry; materials chemistry; applied organic chemistry
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Dr. Carla Rizzo

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Dipartimento di Scienze e Tecnologie Biologiche, Università degli Studi di Palermo, Palermo, Italy
Interests: ionic liquids; supramolecular gels; hybrid supramolecular gels; biomass transformation
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Special Issue Information

Dear Colleagues,

Heterocycles have been, and are still today, the main actors of the pharmaceutical scene. Both as bioactive compounds in the advanced clinical trials stage and as drugs reaching the market, they always play a main role in drug discovery.

Heterocycles are recurrent scaffolds in medicinal chemistry, exploited in drug design and reported in the literature as antibiotics, antivirals, antifungals, antitumorals, antioxidants, neuroprotective agents, etc.

Moreover, heterocyclic scaffolds offer easy synthetic accessibility and properties such as lipophilicity and solubility that positively influence uptake and bioavailability. They are often proposed as bioisosteres of several different functional groups, demonstrating even better biological efficacy.

This Special Issue aims to collect recent developments in research on bioactive heterocyclic compounds. Both natural and synthetic heterocycles, including five-membered aromatic; six-membered aromatic; benzocondensed; polycyclic and non-aromatic heterocycles; metal complexes; molecules containing any heterocyclic moiety and their synthesis, biological activity, mechanism of action and potential application in the pharmaceutical field, will all be considered.

Focused reviews will be included and will utilize the most recent literature (last five years).

Dr. Ivana Pibiri
Dr. Carla Rizzo
Guest Editors

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Keywords

aromatic heterocycles
non-aromatic heterocycles
bioactive compounds
drug design
drug discovery

Published Papers (3 papers)

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Research

18 pages, 3760 KiB

Open AccessArticle

Inhibition of Shikimate Kinase from Methicillin-Resistant Staphylococcus aureus by Benzimidazole Derivatives. Kinetic, Computational, Toxicological, and Biological Activity Studies

by Lluvia Rios-Soto, Alicia Hernández-Campos, David Tovar-Escobar, Rafael Castillo, Erick Sierra-Campos, Mónica Valdez-Solana, Alfredo Téllez-Valencia and Claudia Avitia-Domínguez

Int. J. Mol. Sci. 2024, 25(10), 5077; https://doi.org/10.3390/ijms25105077 - 7 May 2024

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Abstract

Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity (C1 and C2) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA. Full article

(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0)

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19 pages, 4666 KiB

Open AccessArticle

Effect of Trichomonacide 6-Nitro-1H-benzimidazole Derivative Compounds on Expression Level of Metabolic Genes in Trichomonas vaginalis

by Jocelyn Yamin Gutiérrez-Cardona, Ernesto Calderón-Jaimes, Daniel Ortega-Cuellar, Adrián Sánchez-Carrillo, Rosa Angélica Castillo-Rodríguez, Luis Miguel Canseco-Ávila, Luz María Rocha-Ramírez, Víctor Martínez-Rosas, Saúl Gómez-Manzo and Beatriz Hernández-Ochoa

Int. J. Mol. Sci. 2024, 25(8), 4568; https://doi.org/10.3390/ijms25084568 - 22 Apr 2024

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Abstract

The parasite Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease worldwide. This infection often remains asymptomatic and is related to several health complications. The traditional treatment for trichomoniasis is the use of drugs of the 5-nitroimidazole family, such as metronidazole; however, scientific reports indicate an increasing number of drug-resistant strains. Benzimidazole derivatives could offer an alternative in the search for new anti-trichomonas drugs. In this sense, two attractive candidates are the compounds O₂N-BZM7 and O₂N-BZM9 (1H-benzimidazole derivatives), since, through in vitro tests, they have shown a higher trichomonacide activity. In this study, we determined the effect on the expression level of metabolic genes in T. vaginalis. The results show that genes involved in redox balance (NADHOX, G6PD::6PGL) are overexpressed, as well as the gene that participates in the first reaction of glycolysis (CK); on the other hand, structural genes such as ACT and TUB are decreased in expression in trophozoites treated with the compound O₂N-BZM9, which would probably affect its morphology, motility and virulence. These results align with the trichomonacidal activity of the compounds, with benzimidazole O₂N-BZM9 being the most potent, with an IC₅₀ value of 4.8 μM. These results are promising for potential future therapeutic applications. Full article

(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0)

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15 pages, 2936 KiB

Open AccessArticle

Lipophilic Studies and In Silico ADME Profiling of Biologically Active 2-Aminothiazol-4(5H)-one Derivatives

by Małgorzata Redka, Szymon Baumgart, Daria Kupczyk, Tomasz Kosmalski and Renata Studzińska

Int. J. Mol. Sci. 2023, 24(15), 12230; https://doi.org/10.3390/ijms241512230 - 31 Jul 2023

Viewed by 871

Abstract

Pseudothiohydantoin derivatives have a wide range of biological activities and are widely used in the development of new pharmaceuticals. Lipophilicity is a basic, but very important parameter in the design of potential drugs, as it determines solubility in lipids, nonpolar solvents, and makes it possible to predict the ADME profile. The aim of this study was to evaluate the lipophilicity of 28 pseudothiohydantoin derivatives showing the inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) using chromatographic methods. Experimentally, lipophilicity was determined by reverse phase thin layer chromatography (RP-TLC) and reverse phase high-performance liquid chromatography (RP-HPLC). In both methods, methanol was used as the organic modifier of the mobile phase. For each 2-aminothiazol-4(5H)-one derivative, a relationship was observed between the structure of the compound and the values of the lipophilicity parameters (log k_w, R_M0). Experimental lipophilicity values were compared with computer calculated partition coefficient (logP) values. A total of 27 of the 28 tested compounds had a lipophilicity value < 5, which therefore met the condition of Lipinski’s rule. In addition, the in silico ADME assay showed favorable absorption, distribution, metabolism, and excretion parameters for most of the pseudothiohydantoin derivatives tested. The study of lipophilicity and the ADME analysis indicate that the tested compounds are good potential drug candidates. Full article

(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0)

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