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Synthesis and In Silico Docking Study towards M-Pro of Novel Heterocyclic Compounds Derived from Pyrazolopyrimidinone as Putative SARS-CoV-2 Inhibitors.

ABSTRACT: In addition to vaccines, antiviral drugs are essential in order to suppress COVID-19. Although some inhibitor candidates have been determined to target the SARS-CoV-2 protein, there is still an urgent need to continue researching novel inhibitors of the SARS-CoV-2 main protease 'Omicron P132H', a protein that has recently been discovered. In the present study, in the search for therapeutic alternatives to treat COVID-19 and its recent variants, we conducted a structure-based virtual screening using docking studies for a new series of pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives 5-13, which were synthesized from the condensation reaction of pyrazolopyrimidinone-hydrazide (4) with a series of electrophiles. Some significant ADMET predictions-in addition to the docking results-were obtained based on the types of interactions formed and the binding energy values were compared to the reference anti- SARS-CoV-2 redocked drug nirmatrelvir.

SUBMITTER: Horchani M

PROVIDER: S-EPMC9416631 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Synthesis and In Silico Docking Study towards M-Pro of Novel Heterocyclic Compounds Derived from Pyrazolopyrimidinone as Putative SARS-CoV-2 Inhibitors.

Horchani Mabrouk M Heise Niels V NV Csuk René R Ben Jannet Hichem H Harrath Abdel Halim AH Romdhane Anis A

Molecules (Basel, Switzerland) 20220819 16

In addition to vaccines, antiviral drugs are essential in order to suppress COVID-19. Although some inhibitor candidates have been determined to target the SARS-CoV-2 protein, there is still an urgent need to continue researching novel inhibitors of the SARS-CoV-2 main protease 'Omicron P132H', a protein that has recently been discovered. In the present study, in the search for therapeutic alternatives to treat COVID-19 and its recent variants, we conducted a structure-based virtual screening us ...[more]

PMID: 36014537

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Project description:Two heterocyclic azole compounds, 3-(2,3-dihydrobenzo[d]thiazol-2-yl)-4H-chromen-4-one (SVS1) and 5-(1H-indol-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (SVS2) were obtained unexpectedly from 2-aminothiophenol and 4-oxo-4H-chromene-3-carbaldehyde (for SVS1), and (E)-2-((1H-indol-3-yl)methylene)-N-methylhydrazine-1-carbothioamide in the presence of anhydrous FeCl3 (for SVS2), respectively. The compounds were well characterized by analytical and spectroscopic tools. The molecular structures of both the compounds were determined by single crystal X-ray diffraction (XRD) study. The results obtained from density functional theory (DFT) study revealed the molecular geometry and electron distribution of the compounds, which were correlated well with the three-dimensional structures obtained from the single crystal XRD. DMol3 was used to calculate quantum chemical parameters [chemical potential (µ), global hardness (η), global softness (σ), absolute electronegativity (χ) and electrophilicity index (ω)] of SVS1 and SVS2. Molecular docking study was performed to elucidate the binding ability of SVS1 and SVS2 with SARS-CoV-2 main protease and human angiotensin-converting enzyme-2 (ACE-2) molecular targets. Interestingly, the binding efficiency of the compounds with the molecular targets was comparable with that of remdesivir (SARS-CoV-2), chloroquine and hydroxychloroquine. SVS1 showed better docking energy than SVS2. The molecular docking study was complemented by molecular dynamics simulation study of SARS-CoV-2 main protease-SVS1 complex, which further exemplified the binding ability of SVS1 with the target. In addition, SVS1, SVS2 and cisplatin were assessed for their cytotoxicity against a panel of three human cancer cells such as HepG-2 (hepatic carcinoma), T24 (bladder) and EA.hy926 (endothelial), as well as Vero (kidney epithelial cells extracted from an African green monkey) normal cells using MTT assay. The results showed that SVS2 has significant cytotoxicity against HepG-2 and EA.hy926 cells with the IC50 values of 33.8 μM (IC50 = 49.9 μM-cisplatin and 8.6 μM-doxorubicin) and 29.2 (IC50 = 26.6 μM-cisplatin and 3.8 μM-doxorubicin), respectively.

Dataset Information

Synthesis and In Silico Docking Study towards M-Pro of Novel Heterocyclic Compounds Derived from Pyrazolopyrimidinone as Putative SARS-CoV-2 Inhibitors.

Publications

Synthesis and In Silico Docking Study towards M-Pro of Novel Heterocyclic Compounds Derived from Pyrazolopyrimidinone as Putative SARS-CoV-2 Inhibitors.

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