Design and synthesis of diphenyl-1H-imidazole analogs targeting Mpro/3CLpro enzyme of SARS-CoV-2

• Published in: Medicinal chemistry research Vol. 33; no. 9; pp. 1568 - 1577
• Main Authors: Kanhed, Ashish M., Vora, Amisha, Thakkar, Ami, Rudramurthy, Gudepalya Renukaiah, Shandil, Radha Krishan, Harisha, Rajappa, Singh, Mayas, Narayanan, Shridhar
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2024; Springer Nature B.V
• Subjects: Antiviral activity; Antiviral agents; Benzene; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Chemical synthesis; Coronaviruses; COVID-19; Drug development; Enzymes; Imidazole; Inorganic Chemistry; Medicinal Chemistry; Original Research Article; Pharmacology/Toxicology; Public health; Severe acute respiratory syndrome coronavirus 2; Viral diseases; Ancestral SARS-CoV-2 variant; SARS-CoV-2; imidazole; inhibition; Delta variant; 3CL; Diphenyl
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-024-03263-7

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 IC 50 values of 7.7 µM, 12.6 µM, and 11.8 µM, respectively) and the Delta variant (with IC 50 values of 7.4 µM, 13.8 µM, and 12.1 µM, respectively). Moreover, the 3CL pro inhibition IC 50 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.