Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: from benzimidazole to indole scaffolds

Bioorg Med Chem Lett. 2006 Oct 1;16(19):4987-93. doi: 10.1016/j.bmcl.2006.07.074.

Abstract

Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole-tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC(50) approximately 50 nM).

MeSH terms

  • Allosteric Regulation
  • Benzimidazoles / pharmacology*
  • Cell Line
  • Hepacivirus / drug effects*
  • Humans
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • Replicon / drug effects*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Benzimidazoles
  • Indoles
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • RNA-Dependent RNA Polymerase