Design, synthesis, and biological evaluation of thiazoles targeting flavivirus envelope proteins

J Med Chem. 2011 Mar 24;54(6):1704-14. doi: 10.1021/jm1013538. Epub 2011 Feb 28.

Abstract

A series of third-generation analogues of methyl 4-(dibromomethyl)-2-(4-chlorophenyl)thiazole-5-carboxylate (1), which had the most potent antiviral activity among the first- and second-generation compounds, have been synthesized and tested against yellow fever virus using a cell-based assay. The compounds were designed with the objectives of improving metabolic stability, therapeutic index, and antiviral potency. The biological effects of C4 and C5 substitution were examined. The methylthio ester and the dihydroxypropylamide analogues had the best antiviral potencies and improved therapeutic indices and metabolic stabilities relative to the parent compound 1.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Cell Line
  • Cricetinae
  • Dengue Virus / metabolism
  • Drug Design
  • Drug Stability
  • Esters
  • Flavivirus / drug effects*
  • Flavivirus / metabolism
  • Ketones / chemical synthesis
  • Ketones / chemistry
  • Ketones / pharmacology
  • Mesocricetus
  • Models, Molecular
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology
  • Viral Envelope Proteins / chemistry
  • Viral Envelope Proteins / metabolism*
  • Yellow fever virus / drug effects

Substances

  • Amides
  • Antiviral Agents
  • Esters
  • Ketones
  • Thiazoles
  • Viral Envelope Proteins