B-ring modified aurones as promising allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase

Eur J Med Chem. 2014 Jun 10:80:579-92. doi: 10.1016/j.ejmech.2014.04.005. Epub 2014 Apr 4.

Abstract

Following our recent report showing the potential of naturally occurring aurones (2-benzylidenebenzofuran-3(2H)-ones) as anti-hepatitis C virus (HCV) agents, efforts were continued in order to refine the structural requirements for the inhibitory effect on HCV RNA-dependent RNA polymerase (RdRp). In this study, we targeted the B-ring moiety of aurones with the aim to improve structural features associated with higher inhibition of the targeted polymerase. In vitro evaluation of the RdRp inhibitory activity of the 37 newly synthesized compounds pointed out that the replacement of the B-ring with an N-substituted indole moiety induced the highest inhibitory effect. Of these, compounds 31, 40 and 41 were found to be the most active (IC50 = 2.3-2.4 μM). Docking experiments performed with the most active compounds revealed that the allosteric thumb pocket I of RdRp is the binding pocket for aurone analogues.

Keywords: Aurones; Hepatitis C virus; RNA-dependent RNA polymerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Antiviral Agents / pharmacology*
  • Benzofurans / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology*
  • Models, Molecular
  • Protein Conformation
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry*

Substances

  • Antiviral Agents
  • Benzofurans
  • Enzyme Inhibitors
  • aurone
  • RNA-Dependent RNA Polymerase