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Small Molecule Heterocyclic Compounds: Synthesis, Design and Biological Activity
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Small Molecule Heterocyclic Compounds: Synthesis, Design and Biological Activity

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 8689

Special Issue Editors

Dr. Mária Kožurková

E-Mail Website
Guest Editor
Department of Biochemistry, Institute of Chemistry, Faculty of Science, Pavol Jozef Šafárik University in Košice, Košice, Slovakia
Interests: drug-DNA/HSA interaction; topoisomerase inhibition; antiproliferative activity of heterocyclic compound; acridine
Special Issues, Collections and Topics in MDPI journals
Dr. Janka Vašková

E-Mail Website
Guest Editor
Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Tr. SNP 1, 040 11 Košice, Slovak Republic
Interests: antioxidant; antioxidant enzyme; antioxidant activity; glutathione; humic acids; chelators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Small molecules can be defined as any organic compounds with a low molecular weight. The wide spectrum of biological properties displayed by molecules with heterocyclic structures have made them much-sought-after targets in the development of a wide range of new drugs. The biological activity of heterocyclic compounds is mainly attributed to the planarity of the aromatic structures, and the position and the nature of the substituents on the heterocyclic core determine the specific properties and selectivity that the compounds exhibit. The design of small molecules capable of interacting with important macromolecules in cells could open up new possibilities for treating different diseases.

This Special Issue will examine recent discoveries in the study of small compound molecules with heterocyclic structures, focusing on their synthesis, design and biological activity. The Issue also provides an overview of the latest findings in the development of agents based on naturally occurring and synthetic heterocycles, offering detailed descriptions of clinical trial results. 

Dr. Mária Kožurková
Dr. Janka Vašková
Guest Editors

Manuscript Submission Information

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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.

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

  • small molecules
  • heterocycle
  • synthesis
  • biological activity

Published Papers (4 papers)

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Research

26 pages, 3734 KiB  
Article
Synthesis and Molecular Docking Studies of Alkoxy- and Imidazole-Substituted Xanthones as α-Amylase and α-Glucosidase Inhibitors
by Dolores G. Aguila-Muñoz, Gabriel Vázquez-Lira, Erika Sarmiento-Tlale, María C. Cruz-López, Fabiola E. Jiménez-Montejo, Víctor E. López y López, Carlos H. Escalante, Dulce Andrade-Pavón, Omar Gómez-García, Joaquín Tamariz and Aarón Mendieta-Moctezuma
Molecules 2023, 28(10), 4180; https://doi.org/10.3390/molecules28104180 - 18 May 2023
Cited by 2 | Viewed by 2196
Abstract
Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro [...] Read more.
Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds 6c, 6e, and 9b promoted higher α-glucosidase inhibition (IC50 = 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC50 = 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC50 = 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives 10c and 10f showed higher α-amylase inhibition (IC50 = 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC50 = 232.7 and 145.2 µM, respectively). According to the structure–activity relationship, attaching 4-bromobutoxy or 4′-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-glucosidase inhibition and lower α-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that 6c, 9b, and 10c are mainly mixed inhibitors on α-glucosidase and α-amylase. In addition, drug prediction and ADMET studies support that compounds 6c, 9b, and 10c are candidates with antidiabetic potential. Full article
(This article belongs to the Special Issue Small Molecule Heterocyclic Compounds: Synthesis, Design and Biological Activity)
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25 pages, 83283 KiB  
Article
An Insight into the Metabolism of 2,5-Disubstituted Monotetrazole Bearing Bisphenol Structures: Emerging Bisphenol A Structural Congeners
by Umesh B. Gadgoli, Yelekere C. Sunil Kumar and Deepak Kumar
Molecules 2023, 28(3), 1465; https://doi.org/10.3390/molecules28031465 - 2 Feb 2023
Viewed by 1518
Abstract
The non-estrogenic 2,5-disubstituted tetrazole core-bearing bisphenol structures (TbB) are being researched as emerging structural congeners of Bisphenol A, an established industrial endocrine disruptor. However, there is no understanding of TbB’s adverse effects elicited via metabolic activation. Therefore, the current study aimed to investigate [...] Read more.
The non-estrogenic 2,5-disubstituted tetrazole core-bearing bisphenol structures (TbB) are being researched as emerging structural congeners of Bisphenol A, an established industrial endocrine disruptor. However, there is no understanding of TbB’s adverse effects elicited via metabolic activation. Therefore, the current study aimed to investigate the metabolism of TbB ligands, with in silico results serving as a guide for in vitro studies. The Cytochrome P450 enzymes (CYP) inhibitory assay of TbB ligands on the seven human liver CYP isoforms (i.e., 1A2, 2A6, 2D6, 2C9, 2C8, 2C19, and 3A4) using human liver microsomes (HLM) revealed TbB ligand 223-3 to have a 50% inhibitory effect on all the CYP isoforms at a 10 μM concentration, except 1A2. The TbB ligand 223-10 inhibited 2B6 and 2C8, whereas the TbB ligand 223-2 inhibited only 2C9. The first-order inactivity rate constant (Kobs) studies indicated TbB ligands 223-3, 223-10 to be time-dependent (TD) inhibitors, whereas the TbB 223-2 ligand did not show such a significant effect. The 223-3 exhibited a TD inhibition for 2C9, 2C19, and 1A2 with Kobs values of 0.0748, 0.0306, and 0.0333 min−1, respectively. On the other hand, the TbB ligand 223-10 inhibited 2C9 in a TD inhibition manner with Kobs value 0.0748 min−1. However, the TbB ligand 223-2 showed no significant TD inhibition effect on the CYPs. The 223-2 ligand biotransformation pathway by in vitro studies in cryopreserved human hepatocytes suggested the clearance via glucuronidation with the predominant detection of only 223-2 derived mono glucuronide as a potential inactive metabolite. The present study demonstrated that the 223-2 ligand did not elicit any significant adverse effect via metabolic activation, thus paving the way for its in vivo drug–drug interactions (DDI) studies. Full article
(This article belongs to the Special Issue Small Molecule Heterocyclic Compounds: Synthesis, Design and Biological Activity)
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25 pages, 5860 KiB  
Article
Novel 3,9-Disubstituted Acridines with Strong Inhibition Activity against Topoisomerase I: Synthesis, Biological Evaluation and Molecular Docking Study
by Kristína Krochtová, Annamária Halečková, Ladislav Janovec, Michaela Blizniaková, Katarína Kušnírová and Mária Kožurková
Molecules 2023, 28(3), 1308; https://doi.org/10.3390/molecules28031308 - 30 Jan 2023
Cited by 2 | Viewed by 1758
Abstract
A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a–17j, in a moderate yield. The principles of cheminformatics and computational chemistry [...] Read more.
A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a–17j, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81–9.03 × 104 M−1) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a–17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a–17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7–GI50 18.6 nM) and N,N-dimethylaniline acridine 17b (SR–GI50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a, 17b, and 17e–17h) and their values of KB, LogP, ΔS°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives. Full article
(This article belongs to the Special Issue Small Molecule Heterocyclic Compounds: Synthesis, Design and Biological Activity)
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16 pages, 2206 KiB  
Article
Synthesis, Spectroscopic Characterization, Antibacterial Activity, and Computational Studies of Novel Pyridazinone Derivatives
by Said Daoui, Şahin Direkel, Munjed M. Ibrahim, Burak Tüzün, Tarik Chelfi, Mohammed Al-Ghorbani, Mustapha Bouatia, Miloud El Karbane, Anass Doukkali, Noureddine Benchat and Khalid Karrouchi
Molecules 2023, 28(2), 678; https://doi.org/10.3390/molecules28020678 - 9 Jan 2023
Cited by 8 | Viewed by 2582
Abstract
In this work, a novel series of pyridazinone derivatives (3–17) were synthesized and characterized by NMR (1H and 13C), FT-IR spectroscopies, and ESI-MS methods. All synthesized compounds were screened for their antibacterial activities against Staphylococcus aureus [...] Read more.
In this work, a novel series of pyridazinone derivatives (3–17) were synthesized and characterized by NMR (1H and 13C), FT-IR spectroscopies, and ESI-MS methods. All synthesized compounds were screened for their antibacterial activities against Staphylococcus aureus (Methicillin-resistant), Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, and Acinetobacter baumannii. Among the series, compounds 7 and 13 were found to be active against S. aureus (MRSA), P. aeruginosa, and A. baumannii with the lowest MIC value range of 3.74–8.92 µM. Afterwards, DFT calculations of B3LYP/6-31++G(d,p) level were carried out to investigate geometry structures, frontier molecular orbital, molecular electrostatic potential maps, and gap energies of the synthesized compounds. In addition, the activities of these compounds against various bacterial proteins were compared with molecular-docking calculations. Finally, ADMET studies were performed to investigate the possibility of using of the target compounds as drugs. Full article
(This article belongs to the Special Issue Small Molecule Heterocyclic Compounds: Synthesis, Design and Biological Activity)
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