Structure-Activity Relationship Studies of SARS-CoV-2 Main Protease Inhibitors Containing 4-Fluorobenzothiazole-2-carbonyl Moieties.

The main protease (M pro ) of SARS-CoV-2 is an attractive target for the development of drugs to treat COVID-19. Here, we report the design, synthesis, and structure-activity relationship (SAR) studies of highly potent SARS-CoV-2 M pro inhibitors including TKB245 ( 5 )/TKB248 ( 6 ). Since we have previously developed M pro inhibitors ( 3 ) and ( 4 ), several hybrid molecules of these previous compounds combined with nirmatrelvir ( 1 ) were designed and synthesized. Compounds such as TKB245 ( 5 ) and TKB248 ( 6 ), containing a 4-fluorobenzothiazole moiety at the P1' site, are highly effective in the blockade of SARS-CoV-2 replication in VeroE6 cells. Replacement of the P1-P2 amide with the thioamide surrogate in TKB248 ( 6 ) improved its PK profile in mice compared to that of TKB245 ( 5 ). A new diversity-oriented synthetic route to TKB245 ( 5 ) derivatives was also developed. The results of the SAR studies suggest that TKB245 ( 5 ) and TKB248 ( 6 ) are useful lead compounds for the further development of M pro inhibitors.