Pyrimidine sulfonylacetanilides with improved potency against key mutant viruses of HIV-1 by specific targeting of a highly conserved residue

Eur J Med Chem. 2015 Sep 18:102:215-22. doi: 10.1016/j.ejmech.2015.08.007. Epub 2015 Aug 7.

Abstract

Based on molecular simulation, the etravirine-VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs.

Keywords: Antiviral agent; Biological activity; Highly conserved residue; Molecular hybridization; Molecular simulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemical synthesis*
  • Acetanilides / chemistry
  • Acetanilides / pharmacology*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Conserved Sequence / drug effects*
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • HIV-1 / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mutation*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Acetanilides
  • Anti-HIV Agents
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • thioacetanilide