Discovery of 2-(4-sulfonamidophenyl)-indole 3-carboxamides as potent and selective inhibitors with broad hepatitis C virus genotype activity targeting HCV NS4B

Bioorg Med Chem Lett. 2016 Jan 15;26(2):594-601. doi: 10.1016/j.bmcl.2015.11.065. Epub 2015 Nov 19.

Abstract

A novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides was identified and optimized for activity against the HCV genotype 1b replicon resulting in compounds with potent and selective activity. Further evaluation of this series demonstrated potent activity across HCV genotypes 1a, 2a and 3a. Compound 4z had reduced activity against HCV genotype 1b replicons containing single mutations in the NS4B coding sequence (F98C and V105M) indicating that NS4B is the target. This novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides serves as a promising starting point for a pan-genotype HCV discovery program.

Keywords: 2-(4-Sulfonamidophenyl)-indole 3-carboxamides; HCV inhibitor; NS4B; Replicon.

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Hepacivirus / chemistry
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Hepacivirus / metabolism
  • Hepatitis C / drug therapy
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Molecular Sequence Data
  • Mutation
  • Replicon / drug effects
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*

Substances

  • Antiviral Agents
  • Indoles
  • NS4B protein, flavivirus
  • Sulfonamides
  • Viral Nonstructural Proteins