Design and synthesis of heterocyclic azole-based bioactive compounds: molecular structures, quantum simulation and mechanistic studies by docking as multi-target inhibitors of SARS-CoV-2 and cytotoxicity

J. Mol Struct. October 21, 2021: 131782. doi: 10.1016 / j.molstruc.2021.131782. Online before printing.

ABSTRACT

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-triazol-3-thione (SVS2) were unexpectedly obtained 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 (to the SVS2), or the compounds were well characterized by analytical and spectroscopic tools. The molecular structures of both compounds were determined by single crystal X-ray diffraction (X-RD). The results of the density functional theory (DFT) study revealed the molecular geometry and electron distribution of the compounds, which were well correlated with the three-dimensional structures obtained from single crystal X-ray diffraction. DMol³ was used to calculate quantum chemical parameters [chemical potential (µ), global hardness (η), global softness (σ), absolute electronegativity (χ) and electrophilicity index (ω)] from SVS1 and SVS2. A molecular docking study was performed to determine the binding ability of SVS1 and SVS2 with SARS-CoV-2 main protease and molecular targets of human angiotensin converting enzyme-2 (ACE-2). Interestingly, the binding efficiency of the compounds with the molecular targets was comparable to that of remdesivir (SARS-CoV-2), chloroquine and hydroxychloroquine. SVS1 showed better docking energy than SVS2. The molecular docking study was supplemented by a molecular dynamic simulation study of the SARS-CoV-2 main protease.SVS1 Complex that has the ability to bind SVS1 with the aim of. Additionally, SVS1, SVS2 and cisplatin were examined for their cytotoxicity against a panel of three human cancer cells such as HepG-2 (liver carcinoma), T24 (bladder) and EA.hy926 (endothelium), and Vero (kidney epithelial cells extracted from an African green monkey) using normal cells of the 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 or 3.8 µM-doxorubicin).

PMID:34697505 | PMC:PMC8528790 | DOI:10.1016 / j.molstruc.2021.131782