Design and synthesis of Diphenyl-1H-imidazole analogs towards SARS CoV-2 3CLpro inhibition for the treatment of COVID-19

Abstract COVID-19 caused by novel corona virus (SARS-CoV-2) is the major pandemic of the decade claiming millions of lives causing severe disruptions to society. Despite rapid development of COVID-19 vaccines, condition is still not under control and newer antiviral drugs are required. In the present work, we describe the design and synthesis of Diphenyl-1H-imidazole derivatives as a potential lead series for SARS-CoV-2 3CLpro enzyme inhibition. The synthesized molecules were screened for SARS-CoV-2 3CLpro enzyme inhibition at 20µM concentration. All the synthesized compounds (6-14) showed inhibition in the range of 88 to 99%. They were further tested for anti-SARS-CoV-2 activity against ancestral Wuhan and the Delta variants in virus infected cells. The compounds 4-(4-hlorophenyl)-2-(3,4-dimethoxyphenyl)-1H-imidazole (9), 4-(2,4-dichlorophenyl)-2-(3,4-dimethoxyphenyl)-1H-imidazole (10), 4-(4-(2,4-dichlorophenyl)-1H-imidazol-2-yl)benzene-1,2-diol (14) showed promising activity against both Wuhan (IC50: 7.7 µM, 12.6 µM and 11.8 µM, respectively) and Delta (IC50: 7.4 µM, 13.8 µM and 12.1 µM, respectively) variant of COVID-19. Our results demonstrate efficacy of diphenyl-1H-imidazole derivatives as promising ligands for further development and optimization against COVID-19.