Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors

Bioorg Med Chem Lett. 2008 Oct 15;18(20):5684-8. doi: 10.1016/j.bmcl.2008.08.082. Epub 2008 Aug 28.

Abstract

Design, synthesis and biological evaluation of a series of 5-chloropyridine ester-derived severe acute respiratory syndrome-coronavirus chymotrypsin-like protease inhibitors is described. Position of the carboxylate functionality is critical to potency. Inhibitor 10 with a 5-chloropyridinyl ester at position 4 of the indole ring is the most potent inhibitor with a SARS-CoV 3CLpro IC(50) value of 30 nM and an antiviral EC(50) value of 6.9 microM. Molecular docking studies have provided possible binding modes of these inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Catalytic Domain
  • Chemistry, Pharmaceutical / methods*
  • Cysteine Endopeptidases / chemistry
  • Drug Design
  • Esters
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • SARS Virus / metabolism*
  • Viral Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Esters
  • Viral Proteins
  • 3C-like proteinase, Coronavirus
  • Cysteine Endopeptidases