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

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.
Kohei Tsuji 1,  Takuya Kobayakawa 1,  Nobuyo Higashi-Kuwata 2,  Takahiro Ishii 1,  Kouki Shinohara 1,  Ryusei Yamamoto 1,  Yutaro Miura 1,  Naoya Wada 1,  Hiroaki Mitsuya 2 3 4,  Hirokazu Tamamura 1
Affiliations

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.
PMID: 40978346 DOI: 10.1021/acsomega.5c05168
Abstract

Development of anti-SARS-CoV-2 agents is still required because of the appearance of drug-resistant strains, and targeting the main protease (Mpro) of SARS-CoV-2 is a powerful way to develop therapeutics against COVID-19. To date, we have developed several Mpro 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 Mpro 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 HeLahACE2‑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 Mpro inhibitors.

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