Design, synthesis, and evaluation of inhibitors for severe acute respiratory syndrome 3C-like protease based on phthalhydrazide ketones or heteroaromatic esters

J Med Chem. 2007 Apr 19;50(8):1850-64. doi: 10.1021/jm061425k. Epub 2007 Mar 24.

Abstract

The 3C-like protease (3CLpro), which controls the severe acute respiratory syndrome (SARS) coronavirus replication, has been identified as a potential target for drug design in the treatment of SARS. A series of tetrapeptide phthalhydrazide ketones, pyridinyl esters, and their analogs have been designed, synthesized, and evaluated as potential SARS 3CLpro inhibitors. Some pyridinyl esters are identified as very potent inhibitors, with IC50 values in the nanomolar range (50-65 nM). Electrospray mass spectrometry indicates a mechanism involving acylation of the active site cysteine thiol for this class of inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Binding Sites
  • Biomimetics
  • Combinatorial Chemistry Techniques
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / chemistry*
  • Esters
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Phthalazines / chemical synthesis*
  • Phthalazines / chemistry
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Spectrometry, Mass, Electrospray Ionization
  • Stereoisomerism
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry*

Substances

  • Antiviral Agents
  • Esters
  • Ketones
  • Oligopeptides
  • Phthalazines
  • Pyridines
  • Viral Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases