Tetrazole and triazole as bioisosteres of carboxylic acid: discovery of diketo tetrazoles and diketo triazoles as anti-HCV agents

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4528-31. doi: 10.1016/j.bmcl.2013.06.045. Epub 2013 Jun 26.

Abstract

A series of diketo tetrazoles and diketo triazoles were designed and synthesized as bioisosteres of α,γ-diketo acid, the active site inhibitor of HCV (Hepatitis C virus) polymerase NS5B. Among the synthesized compounds, 4-(4-fluorobenzyloxy)phenyl diketo triazole (30) exhibited anti-HCV activity with an EC50 value of 3.9 μM and an SI value more than 128. The reduction of viral protein and mRNA levels were also validated, supporting the anti-HCV activity of compound 30. These results provide convincing evidence that the diketo tetrazoles and diketo triazoles can be developed as bioisosteres of α,γ-diketo acid to exhibit potent inhibitory activity against HCV.

Keywords: Anti-HCV activity; Bioisosteres; Diketo tetrazoles; Diketo triazoles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hepacivirus / drug effects*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Tetrazoles / chemical synthesis
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Antiviral Agents
  • Carboxylic Acids
  • Tetrazoles
  • Triazoles