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

The main protease (Mpro) 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 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previousl...

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Published inJournal of medicinal chemistry Vol. 66; no. 19; pp. 13516 - 13529
Main Authors Tsuji, Kohei, Ishii, Takahiro, Kobayakawa, Takuya, Higashi-Kuwata, Nobuyo, Shinohara, Kouki, Azuma, Chika, Miura, Yutaro, Nakano, Hiroki, Wada, Naoya, Hattori, Shin-ichiro, Bulut, Haydar, Mitsuya, Hiroaki, Tamamura, Hirokazu
Format Journal Article
LanguageEnglish
Published American Chemical Society 12.10.2023
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Abstract The main protease (Mpro) 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 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed Mpro 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 Mpro inhibitors.
AbstractList The main protease (Mpro) 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 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed Mpro 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 Mpro inhibitors.The main protease (Mpro) 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 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed Mpro 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 Mpro inhibitors.
The main protease (Mpro) 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 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed Mpro 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 Mpro inhibitors.
Author Wada, Naoya
Nakano, Hiroki
Mitsuya, Hiroaki
Miura, Yutaro
Hattori, Shin-ichiro
Tamamura, Hirokazu
Bulut, Haydar
Ishii, Takahiro
Higashi-Kuwata, Nobuyo
Kobayakawa, Takuya
Tsuji, Kohei
Azuma, Chika
Shinohara, Kouki
AuthorAffiliation Kumamoto University Hospital
Department of Refractory Viral Infections
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute
Department of Clinical Sciences
Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering
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Snippet The main protease (Mpro) of SARS-CoV-2 is an attractive target for the development of drugs to treat COVID-19. Here, we report the design, synthesis, and...
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Title Structure–Activity Relationship Studies of SARS-CoV‑2 Main Protease Inhibitors Containing 4‑Fluorobenzothiazole-2-carbonyl Moieties
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