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

Kohei Tsuji; Takahiro Ishii; Takuya Kobayakawa; Nobuyo Higashi-Kuwata; Kouki Shinohara; Chika Azuma; Yutaro Miura; Hiroki Nakano; Naoya Wada; Shin-Ichiro Hattori; Haydar Bulut; Hiroaki Mitsuya; Hirokazu Tamamura

doi:10.1021/acs.jmedchem.3c00777

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

J Med Chem. 2023 Oct 12;66(19):13516-13529. doi: 10.1021/acs.jmedchem.3c00777. Epub 2023 Sep 27.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo 101-0062, Japan.
² Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo 162-8655, Japan.
³ Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
⁴ Department of Clinical Sciences, Kumamoto University Hospital, Chuo-ku, Kumamoto 860-8556, Japan.

PMID: 37756225
DOI: 10.1021/acs.jmedchem.3c00777

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 (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.