Asymmetric Imidazole-4,5-dicarboxamide Derivatives As SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis and Biological Evaluation

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Sep 30

PMID 39345712

Authors

Phuong Nguyen Hoai Huynh

Phatcharin Khamplong

Minh-Hoang Phan

Thanh-Phuc Nguyen

Phuong Ngoc Lan Vu

Quang-Vinh Tang

Phumin Chamsodsai

Supaphorn Seetaha

Truong Lam Tuong

Thien Y Vu

Duc-Duy Vo

Kiattawee Choowongkomon

Cam-Van T Vo

Affiliations

Soon will be listed here.

Abstract

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 by fluorogenic assay with lopinavir, ritonavir, and ebselen as positive references. -(4-Chlorophenyl)-2-methyl-4-(morpholine-4-carbonyl)-1-imidazole-5-carboxamide (5a2) exhibited the highest potency against the SARS-CoV-2 main protease with an IC of 4.79 ± 1.37 μM relative to ebselen with an IC 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.

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