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

Bioorg Med Chem. 2015 Feb 15;23(4):876-90. doi: 10.1016/j.bmc.2014.12.028. Epub 2014 Dec 20.

Abstract

The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) 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 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) 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.

Keywords: Decahydroisoquinolin; Hydrophobic interaction; Inhibitor; SARS 3CL protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Chymases / antagonists & inhibitors*
  • Chymases / chemistry
  • Chymases / metabolism
  • Crystallography, X-Ray
  • Humans
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Molecular Docking Simulation
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • SARS Virus / chemistry
  • SARS Virus / drug effects
  • SARS Virus / enzymology*
  • Severe Acute Respiratory Syndrome / drug therapy
  • Severe Acute Respiratory Syndrome / virology

Substances

  • Antiviral Agents
  • Isoquinolines
  • Protease Inhibitors
  • Chymases