Design and synthesis of isatin derivatives as effective SARS‐CoV ‐2 3CL protease inhibitors
SARS‐CoV‐2 chymotrypsin‐like cysteine protease (3CLpro) is one of the most widely developed drug targets for COVID‐19. This study aimed to design and synthesize isatin derivatives to target SARS‐CoV‐2 3CLpro in a covalent binding manner. Through the process, a potent 3CLpro inhibitor (5g) was discovered with an IC50 value of 0.43 ± 0.17 μM. To understand the binding affinity and specificity of 5g as a candidate inhibitor of SARS‐CoV‐2 3CLpro, several assays were conducted, including FRET enzyme activity assays, thermodynamic‐based and kinetic‐based validation of inhibitor‐target interactions, and cell‐based FlipGFP assays. The interaction mechanism between 3CLpro‐5g was characterized by docking. Overall, these findings suggest that 5g is a new potent SARS‐CoV‐2 3CLpro inhibitor for the treatment of COVID‐19.
