Integrating in vitro and in silico correlation of thiazole-based carboxamide derivatives as promising SARS-CoV-2 papain-like protease inhibitors: a versatile approach for COVID-19 therapy

Abstract A new series of thiazole-based carboxamide derivatives ( 5–12 ) was designed, synthesized with structural elucidation performed using standard spectroscopic techniques including NMR and HRMS. The synthesized compounds were evaluated for their inhibitory activity against SARS-CoV-2 papain-like protease (PL pro ) and compared with the reference inhibitor GRL0617 (IC 50  = 2.73 ± 2.20 µM). Among the tested compounds, compounds (8) (IC 50  = 1.94 ± 1.50 µM) and (6) (IC 50  = 2.53 ± 1.90 µM) exhibited the most potent inhibitory activity, outperforming or matching the reference inhibitor, while the remaining compounds showed moderate to good PLpro inhibition. Structure–activity relationship analysis was supported by molecular docking studies, which demonstrated that compound 8 possessed the strongest binding affinity (−7.875 kcal/mol), forming key hydrogen bonds with Gly163 and Gly271. Compound (6) also showed favorable binding (−7.426 kcal/mol), establishing similar hydrogen bonding interactions together with additional hydrophobic contacts within the active site. Density functional theory (DFT) calculations provided insights into the electronic properties underlying molecular reactivity and stability, whereas in silico ADME analysis predicted favorable pharmacokinetic characteristics and drug-likeness. Collectively, these experimental and computational findings identify thiazole-based carboxamide derivatives, particularly compounds (8) and (6) , as promising candidates for the development of potent SARS-CoV-2 PL pro inhibitors.