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Recent Advances: Heterocycles in Drugs and Drug Discovery

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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: closed (30 April 2023) | Viewed by 18879

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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
Special Issues, Collections and Topics in MDPI journals

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 and so on.

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 with even better biological efficacy.

This Special Issue aims to collect recent developments of the 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 be considered.

Focused reviews will be included, embracing the very recent literature (last five years).

Dr. Ivana Pibiri
Guest Editor

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Keywords

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

Published Papers (10 papers)

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Research

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36 pages, 17078 KiB

Open AccessArticle

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids

by Sara F. Vieira, Joana Araújo, Virgínia M. F. Gonçalves, Carla Fernandes, Madalena Pinto, Helena Ferreira, Nuno M. Neves and Maria Elizabeth Tiritan

Int. J. Mol. Sci. 2023, 24(12), 10357; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210357 - 19 Jun 2023

Cited by 1 | Viewed by 1516

Abstract

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2–31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32–61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered. Full article

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

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12 pages, 1600 KiB

Open AccessArticle

Photoactivatable Heptamethine-Based Carbonic Anhydrase Inhibitors Leading to New Anti-Antibacterial Agents

by Simone Carradori, Andrea Angeli, Patrick S. Sfragano, Xheila Yzeiri, Massimo Calamante, Damiano Tanini, Antonella Capperucci, Hannah Kunstek, Mihayl Varbanov, Clemente Capasso and Claudiu T. Supuran

Int. J. Mol. Sci. 2023, 24(11), 9610; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119610 - 1 Jun 2023

Cited by 5 | Viewed by 1123

Abstract

With the aim to propose innovative antimicrobial agents able to not only selectively inhibit bacterial carbonic anhydrases (CAs) but also to be photoactivated by specific wavelengths, new heptamethine-based compounds decorated with a sulfonamide moiety were synthesized by means of different spacers. The compounds displayed potent CA inhibition and a slight preference for bacterial isoforms. Furthermore, minimal inhibitory and bactericidal concentrations and the cytotoxicity of the compounds were assessed, thus highlighting a promising effect under irradiation against S. epidermidis. The hemolysis activity test showed that these derivatives were not cytotoxic to human red blood cells, further corroborating their favorable selectivity index. This approach led to the discovery of a valuable scaffold for further investigations. Full article

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

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25 pages, 4973 KiB

Open AccessArticle

Design, Synthesis, Antiproliferative Actions, and DFT Studies of New Bis–Pyrazoline Derivatives as Dual EGFR/BRAF^V600E Inhibitors

by Lamya H. Al-Wahaibi, Hesham A. Abou-Zied, Eman A. M. Beshr, Bahaa G. M. Youssif, Alaa M. Hayallah and Mohamed Abdel-Aziz

Int. J. Mol. Sci. 2023, 24(10), 9104; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24109104 - 22 May 2023

Cited by 6 | Viewed by 1699

Abstract

Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAF^V600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI₅₀ values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAF^V600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAF^V600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAF^V600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study. Full article

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

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25 pages, 2537 KiB

Open AccessArticle

Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates

by Olaia Martí-Marí, Rana Abdelnabi, Dominique Schols, Johan Neyts, María-José Camarasa, Federico Gago and Ana San-Félix

Int. J. Mol. Sci. 2023, 24(4), 3539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043539 - 10 Feb 2023

Cited by 2 | Viewed by 1649

Abstract

AL-471, the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four l-tryptophan (Trp) units bearing an aromatic isophthalic acid directly attached to the C2 position of each indole ring. Starting from AL-471, we (i) replaced l-Trp with d-Trp, (ii) inserted a flexible linker between C2 and the isophthalic acid, and (iii) substituted a nonaromatic carboxylic acid for the terminal isophthalic acid. Truncated analogues lacking the Trp motif were also synthesized. Our findings indicate that the antiviral activity seems to be largely independent of the stereochemistry (l- or d-) of the Trp fragment and also that both the Trp unit and the distal isophthalic moiety are essential for antiviral activity. The most potent derivative, 23 (AL-534), with the C2 shortest alkyl urea linkage (three methylenes), showed subnanomolar potency against different EV-71 clinical isolates. This finding was only observed before with the early dendrimer prototype AL-385 (12 l-Trp units) but remained unprecedented for the reduced-size prototype AL-471. Molecular modeling showed the feasibility of high-affinity binding of the novel l-Trp-decorated branches of 23 (AL-534) to an alternative site on the VP1 protein that harbors significant sequence variation among EV-71 strains. Full article

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

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15 pages, 3026 KiB

Open AccessArticle

Assessment of the Permeability of 3,4-Methylenedioxypyrovalerone (MDPV) across the Caco-2 Monolayer for Estimation of Intestinal Absorption and Enantioselectivity

by Ana Sofia Almeida, Bárbara Silva, Fernando Remião and Carla Fernandes

Int. J. Mol. Sci. 2023, 24(3), 2680; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032680 - 31 Jan 2023

Cited by 2 | Viewed by 1393

Abstract

3,4-Methylenedioxypyrovalerone (MDPV) is a widely studied synthetic cathinone heterocycle mainly concerning its psychoactive effects. It is a chiral molecule and one of the most abused new psychoactive substances worldwide. Enantioselectivity studies for MDPV are still scarce and the extent to which it crosses the intestinal membrane is still unknown. Herein, an in vitro permeability study was performed to evaluate the passage of the enantiomers of MDPV across the Caco-2 monolayer. To detect and quantify MDPV, a UHPLC-UV method was developed and validated. Acceptable values within the recommended limits were obtained for all evaluated parameters (specificity, linearity, accuracy, limit of detection (LOD), limit of quantification (LOQ) and precision). The enantiomers of MDPV were found to be highly permeable across the Caco-2 monolayer, which can indicate a high intestinal permeability. Enantioselectivity was observed for the P_app values in the basolateral (BL) to apical (AP) direction. Furthermore, efflux ratios are indicative of efflux through a facilitated diffusion mechanism. To the best of our knowledge, determination of the permeability of MDPV across the intestinal epithelial cell monolayer is presented here for the first time. Full article

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

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22 pages, 2915 KiB

Open AccessArticle

Adamantane-Substituted Purine Nucleosides: Synthesis, Host–Guest Complexes with β-Cyclodextrin and Biological Activity

by Jana Rudolfová, Vladimír Kryštof, Marek Nečas, Robert Vícha and Michal Rouchal

Int. J. Mol. Sci. 2022, 23(23), 15143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315143 - 1 Dec 2022

Cited by 2 | Viewed by 1598

Abstract

Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host–guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity. Full article

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

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20 pages, 2446 KiB

Open AccessArticle

Giardia lamblia G6PD::6PGL Fused Protein Inhibitors Decrease Trophozoite Viability: A New Alternative against Giardiasis

by Laura Morales-Luna, Beatriz Hernández-Ochoa, Víctor Martínez-Rosas, Gabriel Navarrete-Vázquez, Daniel Ortega-Cuellar, Yadira Rufino-González, Abigail González-Valdez, Roberto Arreguin-Espinosa, Adrián Marcelo Franco-Vásquez, Verónica Pérez de la Cruz, Sergio Enríquez-Flores, Carlos Martínez-Conde, Luis Miguel Canseco-Ávila, Fernando Gómez-Chávez and Saúl Gómez-Manzo

Int. J. Mol. Sci. 2022, 23(22), 14358; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214358 - 18 Nov 2022

Cited by 5 | Viewed by 2012

Abstract

Treatments to combat giardiasis have been reported to have several drawbacks, partly due to the drug resistance and toxicity of current antiparasitic agents. These constraints have prompted many researchers to investigate new drugs that act against protozoan parasites. Enzyme inhibition is an important means of regulating pathogen metabolism and has recently been identified as a significant alternative target in the search for new treatments. Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase (G6PD::6PGL) is a bifunctional enzyme involved in the pentose phosphate pathway (PPP) in Giardia lamblia (G. lamblia). The G. lamblia enzyme is unusual since, unlike the human enzyme, it is a fused enzyme. Here, we show, through inhibition assays, that an in-house chemical library of 120 compounds and four target compounds, named CNZ-7, CNZ-8, CMC-1, and FLP-2, are potent inhibitors of the G. lamblia G6PD::6PGL fused enzyme. With a constant (k₂) of 2.3, 3.2, and 2.8 M⁻¹ s⁻¹, respectively, they provoke alterations in the secondary and tertiary protein structure and global stability. As a novel approach, target compounds show antigiardial activity, with IC₅₀ values of 8.7, 15.2, 15.3, and 24.1 µM in trophozoites from G. lamblia. Moreover, these compounds show selectivity against G. lamblia, since, through counter-screening in Caco-2 and HT29 human cells, they were found to have low toxicity. This finding positions these compounds as a potential and attractive starting point for new antigiardial drugs. Full article

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

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17 pages, 1725 KiB

Open AccessArticle

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

by Irene Betancourt-Conde, Claudia Avitia-Domínguez, Alicia Hernández-Campos, Rafael Castillo, Lilián Yépez-Mulia, Jesús Oria-Hernández, Sara T. Méndez, Erick Sierra-Campos, Mónica Valdez-Solana, Siseth Martínez-Caballero, Juan A. Hermoso, Antonio Romo-Mancillas and Alfredo Téllez-Valencia

Int. J. Mol. Sci. 2021, 22(24), 13613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413613 - 19 Dec 2021

Cited by 4 | Viewed by 2667

Abstract

Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I₅₀ values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis. Full article

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

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Review

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14 pages, 1285 KiB

Open AccessReview

Revisiting Cryptocyanine Dye, NK-4, as an Old and New Drug: Review and Future Perspectives

by Shihui Liu, Toshihiko Matsuo and Takumi Abe

Int. J. Mol. Sci. 2023, 24(5), 4411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054411 - 23 Feb 2023

Viewed by 2371

Abstract

NK-4 plays a key role in the treatment of various diseases, such as in hay fever to expect anti-allergic effects, in bacterial infections and gum abscesses to expect anti-inflammatory effects, in scratches, cuts, and mouth sores from bites inside the mouth for enhanced wound healing, in herpes simplex virus (HSV)-1 infections for antiviral effects, and in peripheral nerve disease that causes tingling pain and numbness in hands and feet, while NK-4 is used also to expect antioxidative and neuroprotective effects. We review all therapeutic directions for the cyanine dye NK-4, as well as the pharmacological mechanism of NK-4 in animal models of related diseases. Currently, NK-4, which is sold as an over-the-counter drug in drugstores, is approved for treating allergic diseases, loss of appetite, sleepiness, anemia, peripheral neuropathy, acute suppurative diseases, wounds, heat injuries, frostbite, and tinea pedis in Japan. The therapeutic effects of NK-4’s antioxidative and neuroprotective properties in animal models are now under development, and we hope to apply these pharmacological effects of NK-4 to the treatment of more diseases. All experimental data suggest that different kinds of utility of NK-4 in the treatment of diseases can be developed based on the various pharmacological properties of NK-4. It is expected that NK-4 could be developed in more therapeutic strategies to treat many types of diseases, such as neurodegenerative and retinal degenerative diseases. Full article

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

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9 pages, 692 KiB

Open AccessBrief Report

Microbial Transformations of Halolactones and Evaluation of Their Antiproliferative Activity

by Marcelina Mazur, Karolina Maria Zych, Bożena Obmińska-Mrukowicz and Aleksandra Pawlak

Int. J. Mol. Sci. 2023, 24(8), 7587; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087587 - 20 Apr 2023

Viewed by 1108

Abstract

The microbial transformations of lactones with a halogenoethylocyclohexane moiety were performed in a filamentous fungi culture. The selected, effective biocatalyst for this process was the Absidia glauca AM177 strain. The lactones were transformed into the hydroxy derivative, regardless of the type of halogen atom in the substrate structure. For all lactones, the antiproliferative activity was determined toward several cancer cell lines. The antiproliferative potential of halolactones was much broader than that observed for the hydroxyderivative. According to the presented results, the most potent was chlorolactone, which exhibited significant activity toward the T-cell lymphoma line (CL-1) cell line. The hydroxyderivative obtained through biotransformation was not previously described in the literature. Full article

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

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