Structure-activity relationship studies of thiazole-based derivatives leading to the identification of novel and potent SARS-CoV-2 main protease inhibitors

The COVID-19 pandemic has highlighted the need for effective antiviral agents targeting SARS-CoV-2. This study presents the development of thiazole-based inhibitors against SARS-CoV-2 Main Protease, a key enzyme for viral replication. Using Masitinib and MAC-5576 as leads, we designed 29 compounds featuring a pyridinyl ester for covalent binding to Cys145 and a thiazole core for S2 subsite interaction. Structure-activity relationship (SAR) analysis identified the pyridinyl ester as a critical pharmacophore, with the thiazole core providing superior inhibition compared to oxazole. Compound MC12 (IC₅₀ = 77.7 ± 14.1 nM) demonstrated inhibitory activities comparable to Nirmatrelvir (IC₅₀ = 58.4 ± 8.6 nM). Mass spectrometry and X-ray crystallography confirmed reversible covalent binding of MC compounds to SARS-CoV-2 Main Protease. These compounds also showed low cytotoxicity and dual inhibition of SARS-CoV and SARS-CoV-2 M^pro. Thiazole-based compounds thus emerge as promising leads for developing potent and safe SARS-CoV-2 M^pro inhibitors.