Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors

Yasuhiro Shimamoto, Yasunao Hattori, Kazuya Kobayashi, Kenta Teruya, Akira Sanjoh, Atsushi Nakagawa, Eiki Yamashita, Kenichi Akaji

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CLpro inhibitor. X-ray crystallographic analyses of the SARS 3CLpro in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.

Original languageEnglish
Pages (from-to)876-890
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number4
DOIs
Publication statusPublished - 2015 Feb 15

Keywords

  • Decahydroisoquinolin
  • Hydrophobic interaction
  • Inhibitor
  • SARS 3CL protease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Shimamoto, Y., Hattori, Y., Kobayashi, K., Teruya, K., Sanjoh, A., Nakagawa, A., Yamashita, E., & Akaji, K. (2015). Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors. Bioorganic and Medicinal Chemistry, 23(4), 876-890. https://doi.org/10.1016/j.bmc.2014.12.028