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Bioactive Heterocyclic Compounds in Drug Design
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Bioactive Heterocyclic Compounds in Drug Design

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 23194

Special Issue Editors

Prof. Dr. Antonino Lauria

E-Mail Website
Guest Editor
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

E-Mail Website
Guest Editor
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

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

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

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Published Papers (7 papers)

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Research

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26 pages, 4695 KiB  
Article
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://doi.org/10.3390/molecules28062543 - 10 Mar 2023
Cited by 4 | Viewed by 2136
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules27227786 - 11 Nov 2022
Cited by 5 | Viewed by 3102
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules27196216 - 21 Sep 2022
Cited by 2 | Viewed by 1908
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules27092848 - 29 Apr 2022
Cited by 12 | Viewed by 2756
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 [...] Read more.
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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18 pages, 3238 KiB  
Article
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://doi.org/10.3390/molecules26144309 - 16 Jul 2021
Cited by 2 | Viewed by 3280
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules26113243 - 28 May 2021
Cited by 11 | Viewed by 2685
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 [...] Read more.
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  
Review
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://doi.org/10.3390/molecules26206197 - 14 Oct 2021
Cited by 39 | Viewed by 5915
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 [...] Read more.
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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