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

Abstract

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 (<b>5</b>)/TKB248 (<b>6</b>). Since we have previously developed M^pro inhibitors (<b>3</b>) and (<b>4</b>), several hybrid molecules of these previous compounds combined with nirmatrelvir (<b>1</b>) were designed and synthesized. Compounds such as TKB245 (<b>5</b>) and TKB248 (<b>6</b>), 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 (<b>6</b>) improved its PK profile in mice compared to that of TKB245 (<b>5</b>). A new diversity-oriented synthetic route to TKB245 (<b>5</b>) derivatives was also developed. The results of the SAR studies suggest that TKB245 (<b>5</b>) and TKB248 (<b>6</b>) are useful lead compounds for the further development of M^pro inhibitors.