Design and synthesis of diphenyl-1H-imidazole analogs targeting M^pro/3CL^pro enzyme of SARS-CoV-2

The prevailing COVID-19 pandemic, triggered by the novel coronavirus SARS-CoV-2, stands as the predominant global health crisis of the decade, claiming millions of lives and causing profound disruptions to society. Despite the rapid development of vaccines against COVID-19, the situation remains challenging, necessitating the exploration of new antiviral drugs. In this study, we present the design and synthesis of diphenyl-1H-imidazole derivatives as a potential lead series for inhibiting the SARS-CoV-2 3CL^pro enzyme. The synthesized molecules underwent screening for inhibiting the SARS-CoV-2 3CL^pro enzyme at a concentration of 20 µM. Compounds 6–14 exhibited inhibition ranging from 88 to 99%. Further assessments were conducted to evaluate the anti-SARS-CoV-2 activity of these compounds against both the ancestral SARS-CoV-2 strain and the Delta variant in virus-infected cells. Compounds such as 4-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-1H-imidazole (9), 4-(2,4-dichlorophenyl)-2-(3,4-dimethoxyphenyl)-1H-imidazole (10), and 4-(4-(2,4-dichlorophenyl)-1H-imidazol-2-yl)benzene-1,2-diol (14) exhibited promising activity against both the SARS-CoV-2 strain (with IC₅₀ values of 7.7 µM, 12.6 µM, and 11.8 µM, respectively) and the Delta variant (with IC₅₀ values of 7.4 µM, 13.8 µM, and 12.1 µM, respectively). Moreover, the 3CL^pro inhibition IC₅₀ values for these compounds correlated well with the observed antiviral activity, measuring at 5.1 µM (9), 10.9 µM (10), and 7.3 µM (14). These findings underscore the efficacy of diphenyl-1H-imidazole derivatives as promising candidates for further development and optimization in the fight against COVID-19.