In silico anti-SARS-CoV-2 activities of five-membered heterocycle-substituted benzimidazoles.

The manuscript deals with cost-effective synthesis, structural characterization and in silico SARS-CoV-2 screening activity of 5-membered heterocycle-substituted benzimidazole derivatives, 1-((1H-pyrrol-2-yl)methyl)-2-(1H-pyrrol-2-yl)-1H-benzo[d]imidazole (L1), 2-(furan-2-yl)-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole (L2), 2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole (L3). The benzimidazole compounds were synthesized through a green-synthetic approach by coupling of 5-membered heterocyclic-carboxaldehyde and o-phenylenediamine in water under an aerobic condition. The compounds were characterized by various spectroscopic methods and X-ray structural analysis. The suitable single-crystals of the methyl derivative of L3 were grown as L3' which crystallized in a monoclinic system and the thiophene groups co-existed in a nearly a perpendicular orientation. Further, in silico anti-SARS-CoV-2 proficiency of the synthetic derivatives is evaluated against main protease (Mpro) and non-structural proteins (nsp2 and nsp7) of SARS-CoV-2. Molecular docking and molecular dynamics analysis of the ligands (L1-L3) against Mpro and nsp2 and nsp7 for 50 ns reveal that L3 turns out to be the superlative antiviral candidate against Mpro, nsp2 and nsp7 of SARS-CoV-2 as evident from the binding score and stability of the ligand-docked complexes with considerable binding energy changes.

A benzimidazole scaffold as a promising inhibitor against SARS-CoV-2.

The manuscript reports the green-chemical synthesis of a new diindole-substituted benzimidazole compound, B1 through a straightforward route in coupling between indolyl-3-carboxaldehyde and o-phenylenediamine in water medium under the aerobic condition at 75 ºC. The single crystal X-ray structural analysis of B1 suggests that the disubstituted benzimidazole compound crystallizes in a monoclinic system and the indole groups exist in a perpendicular fashion with respect to benzimidazole moiety. The SARS-CoV-2 screening activity has been studied against 1 × 10e4 VeroE6 cells in a dose-dependent manner following Hoechst 33342 and nucleocapsid staining activity with respect to remdesivir. The compound exhibits 92.4% cell viability for 30 h and 35.1% inhibition against VeroE6 cells at non-cytotoxic concentration. Molecular docking studies predict high binding propensities of B1 with the main protease (Mpro) and non-structural (nsp2 and nsp7-nsp8) proteins of SARS-CoV-2 through a number of non-covalent interactions. Molecular dynamics (MD) simulation analysis for 100 ns confirms the formation of stable conformations of B1-docked proteins with significant changes of binding energy, attributing the potential inhibition properties of the synthetic benzimidazole scaffold against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.