Design and synthesis of Diphenyl-1H-imidazole analogs targeting MPro/3CLpro 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 3CLpro enzyme. The synthesized molecules underwent screening for inhibiting the SARS-CoV-2 3CLpro enzyme at a concentration of 20µM. 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 Wuhan 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 Wuhan 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 3CLpro 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.