Asymmetric imidazole-4,5-dicarboxamide derivatives as SARS-CoV-2 main protease inhibitors: design, synthesis and biological evaluation.

Huynh PNH, Khamplong P, Phan MH, Nguyen TP, Vu PNL, Tang QV, Chamsodsai P, Seetaha S, Tuong TL, Vu TY, Vo DD, Choowongkomon K, Vo CT

RSC Med Chem - (-) - [2024-09-03; online 2024-09-03]

The SARS-CoV-2 main protease, a vital enzyme for virus replication, is a potential target for developing drugs in COVID-19 treatment. Until now, three SARS-CoV-2 main protease inhibitors have been approved for COVID-19 treatment. This study explored the inhibitory potency of asymmetric imidazole-4,5-dicarboxamide derivatives against the SARS-CoV-2 main protease. Fourteen derivatives were designed based on the structure of the SARS-CoV-2 main protease active site, the hydrolysis mechanism, and the experience gained from the reported inhibitor structures. They were synthesized through a four-step procedure from benzimidazole and 2-methylbenzimidazole. SARS-CoV-2 main protease inhibition was evaluated in vitro by fluorogenic assay with lopinavir, ritonavir, and ebselen as positive references. N-(4-Chlorophenyl)-2-methyl-4-(morpholine-4-carbonyl)-1H-imidazole-5-carboxamide (5a2) exhibited the highest potency against the SARS-CoV-2 main protease with an IC50 of 4.79 ± 1.37 μM relative to ebselen with an IC50 of 0.04 ± 0.013 μM. Enzyme kinetic and molecular docking studies were carried out to clarify the inhibitory mechanism and to prove that the compound interacts at the active site. We also performed cytotoxicity assay to confirm that these compounds are not toxic to human cells.

PubMed 39345712

DOI 10.1039/d4md00414k

Crossref 10.1039/d4md00414k

pmc: PMC11423687
pii: d4md00414k