SARS-CoV‑2 Main Protease Inhibitors Containing 5‑Substituted Benzothiazole-2-carbonyl Moieties at the P1' Site and Their Derivatives

Kohei Tsuji; Takuya Kobayakawa; Nobuyo Higashi-Kuwata; Takahiro Ishii; Kouki Shinohara; Ryusei Yamamoto; Yutaro Miura; Naoya Wada; Hiroaki Mitsuya; Hirokazu Tamamura

doi:10.1021/acsomega.5c05168

SARS-CoV‑2 Main Protease Inhibitors Containing 5‑Substituted Benzothiazole-2-carbonyl Moieties at the P1' Site and Their Derivatives

ACS Omega. 2025 Aug 27;10(36):41608-41619. doi: 10.1021/acsomega.5c05168. eCollection 2025 Sep 16.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Chiyoda-ku 101-0062, Tokyo, Japan.
² Department of Refractory Viral Infections, National Institute of Global Health and Medicine, Japan Institute for Health Security, Shinjuku-ku 162-8655, Tokyo, 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 860-8556, Kumamoto, Japan.

Abstract

Development of anti-SARS-CoV-2 agents is still required because of the appearance of drug-resistant strains, and targeting the main protease (M^pro) of SARS-CoV-2 is a powerful way to develop therapeutics against COVID-19. To date, we have developed several M^pro inhibitors including compounds 3, 4, TKB245 (6), and TKB248 (7), which have a 4-fluorobezothiazole ketone moiety as a warhead structure. Further studies led to the development of a more potent M^pro inhibitor, TKB272 (8), which has a 5-fluorobenzothiazole ketone moiety. The slight difference in the introduction position of a fluorine atom enhanced its antiviral activity approximately 3-fold for VeroE6 cells and 15-fold for HeLa^{hACE2‑TMPRSS2} cells when TKB272 (8) was compared to TKB245 (6). Herein, we report the synthesis and structure-activity relationship (SAR) studies of TKB272 (8). TKB272 (8) is a promising drug candidate for COVID-19 therapy, and the present data of the SAR studies are useful for the further development of M^pro inhibitors.