Design, synthesis and computational study of benzimidazole derivatives as potential anti-SARS-CoV-2 agents

As the human world has constantly been plagued by the COVID-19 pandemic since its emergence, researchers have been putting mountain -high efforts into designing new weapons to combat the virus. To join this battle against coronavirus, the present communication explores the synthesis of four benzimidazoles (1-4) from aromatic diamines utilizing two separate synthetic strategies. Afterwards, the synthesized four benzimidazole analogues along with sixteen previously synthesized benzimidazole analogues from our laboratory were subjected to in silico prediction of drug -likeness properties and ADMET (absorption, distribution, metabolism, excretion and toxicity) parameters. Additionally, all the compounds were computationally evaluated through molecular docking analysis against four vital target proteins of SARS-CoV-2 namely the main protease, the papain-like protease, the RNA -dependent RNA polymerase and the spike receptor binding domain to gain insight into the interaction pattern of the ligands with the binding site residues of the protein targets and thus to analyze the SARS-CoV-2 inhibitory proficiency of the synthesized derivatives. Among the studied ligands, compounds 1, 2, 13, 14, 15, 16 and 18 displayed excellent docking scores against two or more protein targets as compared to the established antiviral drugs Nirmatrelvir and Remdesivir. Based on the docking scores, the best four complexes (compound 18-Mpro, compound 2-PLpro, compound 1-RdRp and compound 2-spike-RBD) were subjected to molecular dynamic (MD) simulation to examine the stability of the complexes during the simulation period. This integrated molecular docking and MD simulation study suggested two compounds (1 and 18) that could be evolved as promising candidates for the design and discovery of new anti-SARS-CoV-2 agents.