Enantioselective binding of second generation pyrrolobenzoxazepinones to the catalytic ternary complex of HIV-1 RT wild-type and L100I and K103N drug resistant mutants

Bioorg Med Chem Lett. 2011 Jul 1;21(13):3935-8. doi: 10.1016/j.bmcl.2011.05.020. Epub 2011 May 14.

Abstract

We investigated some pyrrolobenzoxazepinone (PBOs, 3e-i) analogues of early described effective non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT). Enzymological studies of 3e-i enantiomers, with wild type (wt) RT and some drug-resistant mutants, revealed a stereoselective mode of action and selectivity for RT ternary complex. Unexpectedly (+)-3g was found more potent towards the L100I mutant than towards the wt RT, whereas (+)-3h inhibited the K103N mutant and RT wt with comparable potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • Drug Resistance, Viral / drug effects
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1* / genetics
  • HIV-1* / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Mutation
  • Oxazepines / chemistry*
  • Oxazepines / metabolism
  • Oxazepines / pharmacology
  • Pyrroles / chemistry
  • Pyrroles / metabolism
  • Pyrroles / pharmacology
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

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