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Bioactive Heterocyclic Compounds in Drug Design

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 18125

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Special Issue Editors

Prof. Dr. Antonino Lauria

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Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Interests: heterocyclic chemistry; medicinal chemistry; drug design; molecular modeling; cheminformatics tools; organic synthesis; chemical biology; kinase inhibitors; enzyme inhibitors; nucleic acids binders; lead optimization; antitumor agents; antibacterials; antiviral agents
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Annamaria Martorana

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Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Interests: heterocyclic chemistry; medicinal chemistry; drug design; organic synthesis; chemical biology; kinase inhibitors; enzyme inhibitors; nucleic acids binders; lead optimization; antitumor agents; antibacterials; neuroprotective agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heterocycles are heavily involved in life processes. DNA, RNA, proteins, and coenzymes are common examples of fundamental biological macromolecules structured by heterocyclic nuclei.

The biomolecular standpoint of drug action confirms the broad biocompatibility and the versatile aptitude of heterocyclic compounds to mimic endogenous molecules and consequently to interact with biological entities. Moreover, heterocyclic chemistry provides useful tools to modulate polarity, solubility, and hydrogen bonding interactions of molecules, in order to develop improved physiochemical, pharmacological, and pharmacokinetic properties of new druggable candidates.

These features make heterocyclic chemistry one of the major pivots for the development of new drugs, justifying the intense interest of the scientific community in this field.

This Special Issue “Bioactive Heterocyclic Compounds in Drug Design” welcomes the submission of original research articles and reviews featuring recent developments in heterocyclic derivatives able to modulate biological pathways, designed by computational methodologies.

Prof. Antonino Lauria
Prof. Annamaria Martorana
Guest Editors

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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. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Biological pathways
Drug design
Heterocyclic scaffolds
Organic synthesis
In silico methodologies
Natural products
Small molecules

Published Papers (7 papers)

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Research

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26 pages, 4695 KiB

Open AccessArticle

The Novel Chiral 2(5H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity

by Alsu M. Khabibrakhmanova, Roza G. Faizova, Olga A. Lodochnikova, Regina R. Zamalieva, Liliya Z. Latypova, Elena Y. Trizna, Andrey G. Porfiryev, Katsunori Tanaka, Oskar A. Sachenkov, Airat R. Kayumov and Almira R. Kurbangalieva

Molecules 2023, 28(6), 2543; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28062543 - 10 Mar 2023

Cited by 1 | Viewed by 1462

Abstract

Over the past decades, 2(5H)-furanone derivatives have been extensively studied because of their promising ability to prevent the biofilm formation by various pathogenic bacteria. Here, we report the synthesis of a series of optically active sulfur-containing 2(5H)-furanone derivatives and characterize their biological activity. Novel thioethers were obtained by an interaction of stereochemically pure 5-(l)-menthyloxy- or 5-(l)-bornyloxy-2(5H)-furanones with aromatic thiols under basic conditions. Subsequent thioethers oxidation by an excess of hydrogen peroxide in acetic acid resulted in the formation of the corresponding chiral 2(5H)-furanone sulfones. The structure of synthesized compounds was confirmed by IR and NMR spectroscopy, HRMS, and single crystal X-ray diffraction. The leading compound, 26, possessing the sulfonyl group and l-borneol moiety, exhibited the prominent activity against Staphylococcus aureus and Bacillus subtilis with MICs of 8 μg/mL. Furthermore, at concentrations of 0.4–0.5 μg/mL, the sulfone 26 increased two-fold the efficacy of aminoglycosides gentamicin and amikacin against S. aureus. The treatment of the model-infected skin wound in the rat with a combination of gentamicin and sulfone 26 speeded up the bacterial decontamination and improved the healing of the wound. The presented results provide valuable new insights into the chemistry of 2(5H)-furanone derivatives and associated biological activities. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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17 pages, 32183 KiB

Open AccessArticle

Synthesis of 2-Aminopyrimidine Derivatives and Their Evaluation as β-Glucuronidase Inhibitors: In Vitro and In Silico Studies

by Sarosh Iqbal, Nimra Naveed Shaikh, Khalid Mohammed Khan, Shumaila Kiran, Sehrish Naz, Zaheer Ul-Haq, Shahnaz Perveen and M. Iqbal Choudhary

Molecules 2022, 27(22), 7786; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227786 - 11 Nov 2022

Cited by 4 | Viewed by 2110

Abstract

Currently the discovery and development of potent β-glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives 1–27 were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds 1–27 were then evaluated for their β-glucuronidase inhibitory activity, and among them, compound 24 (IC₅₀ = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and β-glucuronidase, in silico study was performed. Conclusively, this study has identified a potent β-glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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27 pages, 6979 KiB

Open AccessArticle

Synthesis and Structure–Activity Relationship Studies of Pyrido [1,2-e]Purine-2,4(1H,3H)-Dione Derivatives Targeting Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis

by Nicolas G. Biteau, Vincent Roy, Cyril Nicolas, Hubert F. Becker, Jean-Christophe Lambry, Hannu Myllykallio and Luigi A. Agrofoglio

Molecules 2022, 27(19), 6216; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27196216 - 21 Sep 2022

Cited by 2 | Viewed by 1470

Abstract

In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named Flavin-Dependent Thymidylate Synthase (FDTS) encoded by the thyX gene was discovered; FDTS is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown pyrido[1,2-e]purine-2,4(1H,3H)-dione analogues. Several synthetics efforts were done to optimize regioselective N¹-alkylation through organopalladium cross-coupling. Modelling of potential hits were performed to generate a model of interaction into the active pocket of FDTS to understand and guide further synthetic modification. All those compounds were evaluated on an in-house in vitro NADPH oxidase assays screening as well as against Mycobacterium tuberculosis ThyX. The highest inhibition was obtained for compound 23a with 84.3% at 200 µM without significant cytotoxicity (CC₅₀ > 100 μM) on PBM cells. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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19 pages, 23741 KiB

Open AccessArticle

Development of 1-(4-(Substituted)piperazin-1-yl)-2-((2-((4-methoxybenzyl)thio)pyrimidin-4-yl)oxy)ethanones That Target Poly (ADP-Ribose) Polymerase in Human Breast Cancer Cells

by Suresha N. Deveshegowda, Prashant K. Metri, Rashmi Shivakumar, Ji-Rui Yang, Shobith Rangappa, Ananda Swamynayaka, Muthu K. Shanmugam, Omantheswara Nagaraja, Mahendra Madegowda, Priya Babu Shubha, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Vijay Pandey, Kwang Seok Ahn, Peter E. Lobie and Basappa Basappa

Molecules 2022, 27(9), 2848; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092848 - 29 Apr 2022

Cited by 5 | Viewed by 2161

Abstract

A number of uracil amides cleave poly (ADP-ribose) polymerase and therefore novel thiouracil amide compounds were synthesized and screened for the loss of cell viability in a human-estrogen-receptor-positive breast cancer cell line. The synthesized compounds exhibited moderate to significant efficacy against human breast cancer cells, where the compound 5e IC₅₀ value was found to be 18 μM. Thouracil amide compounds 5a and 5e inhibited the catalytical activity of PARP1, enhanced cleavage of PARP1, enhanced phosphorylation of H2AX, and increased CASPASE 3/7 activity. Finally, in silico analysis demonstrated that compound 5e interacted with PARP1. Hence, specific thiouracil amides may serve as new drug-seeds for the development of PARP inhibitors for use in oncology. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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Graphical abstract

18 pages, 3238 KiB

Open AccessArticle

Antiproliferative Properties and G-Quadruplex-Binding of Symmetrical Naphtho[1,2-b:8,7-b’]dithiophene Derivatives

by Antonino Lauria, Gabriele La Monica, Alessio Terenzi, Giuseppe Mannino, Riccardo Bonsignore, Alessia Bono, Anna Maria Almerico, Giampaolo Barone, Carla Gentile and Annamaria Martorana

Molecules 2021, 26(14), 4309; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26144309 - 16 Jul 2021

Cited by 2 | Viewed by 2807

Abstract

Background: G-quadruplex (G4) forming sequences are recurrent in telomeres and promoter regions of several protooncogenes. In normal cells, the transient arrangements of DNA in G-tetrads may regulate replication, transcription, and translation processes. Tumors are characterized by uncontrolled cell growth and tissue invasiveness and some of them are possibly mediated by gene expression involving G-quadruplexes. The stabilization of G-quadruplex sequences with small molecules is considered a promising strategy in anticancer targeted therapy. Methods: Molecular virtual screening allowed us identifying novel symmetric bifunctionalized naphtho[1,2-b:8,7-b’]dithiophene ligands as interesting candidates targeting h-Telo and c-MYC G-quadruplexes. A set of unexplored naphtho-dithiophene derivatives has been synthesized and biologically tested through in vitro antiproliferative assays and spectroscopic experiments in solution. Results: The analysis of biological and spectroscopic data highlighted noteworthy cytotoxic effects on HeLa cancer cell line (GI₅₀ in the low μM range), but weak interactions with G-quadruplex c-MYC promoter. Conclusions: The new series of naphtho[1,2-b:8,7-b’]dithiophene derivatives, bearing the pharmacophoric assumptions necessary to stabilize G-quadruplexes, have been designed and successfully synthesized. The interesting antiproliferative results supported by computer aided rational approaches suggest that these studies are a significant starting point for a lead optimization process and the isolation of a more efficacious set of G-quadruplexes stabilizers. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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12 pages, 5288 KiB

Open AccessArticle

Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation

by Ai-Ling Sun, Wen-Wen Mu, Yan-Mo Li, Ya-Lei Sun, Peng-Xiao Li, Ren-Min Liu, Jie Yang and Guo-Yun Liu

Molecules 2021, 26(11), 3243; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26113243 - 28 May 2021

Cited by 8 | Viewed by 2240

Abstract

Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electron-withdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2–C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2–C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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Review

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56 pages, 86558 KiB

Open AccessReview

Plant-Based Natural Products and Extracts: Potential Source to Develop New Antiviral Drug Candidates

by Eyana Thomas, Laura E. Stewart, Brien A. Darley, Ashley M. Pham, Isabella Esteban and Siva S. Panda

Molecules 2021, 26(20), 6197; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206197 - 14 Oct 2021

Cited by 29 | Viewed by 4623

Abstract

Viral infections are among the most complex medical problems and have been a major threat to the economy and global health. Several epidemics and pandemics have occurred due to viruses, which has led to a significant increase in mortality and morbidity rates. Natural products have always been an inspiration and source for new drug development because of their various uses. Among all-natural sources, plant sources are the most dominant for the discovery of new therapeutic agents due to their chemical and structural diversity. Despite the traditional use and potential source for drug development, natural products have gained little attention from large pharmaceutical industries. Several plant extracts and isolated compounds have been extensively studied and explored for antiviral properties against different strains of viruses. In this review, we have compiled antiviral plant extracts and natural products isolated from plants reported since 2015. Full article

(This article belongs to the Special Issue Bioactive Heterocyclic Compounds in Drug Design)

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