Specific targeting of highly conserved residues in the HIV-1 reverse transcriptase primer grip region. 2. Stereoselective interaction to overcome the effects of drug resistant mutations

J Med Chem. 2009 Feb 26;52(4):1224-8. doi: 10.1021/jm801395v.


Starting from the prototypic compound 4, we describe new, potent, and broad-spectrum pyrrolobenzo(pyrido)oxazepinones antivirals. A biochemical and enzymological investigation was performed for defining their mechanism of inhibition at either recombinant HIV-1 RT wild type and non-nucleoside reverse transcriptase inhibitors (NNRTIs)-resistant mutants. For the novel compounds (S)-(+)-5 and (S)-(-)-7, a clear-cut stereoselective mechanism of enzyme inhibition was found. Molecular modeling studies were performed for revealing the underpinnings of this behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Conserved Sequence
  • Drug Resistance / drug effects*
  • Drug Resistance / genetics
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Humans
  • Models, Molecular
  • Mutation
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase