Pyrrolobenzoxazepinone derivatives as non-nucleoside HIV-1 RT inhibitors: further structure-activity relationship studies and identification of more potent broad-spectrum HIV-1 RT inhibitors with antiviral activity

J Med Chem. 1999 Oct 21;42(21):4462-70. doi: 10.1021/jm990150o.


Pyrrolobenzoxazepinone (PBO) derivatives represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTs) whose prototype is (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)- one (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis and biological evaluation of novel derivatives and analogues of 6 featuring a meta-substituted phenyl or a 2-thienyl ring at C-6 and a pyridine system in place of the fused-benzene ring to yield pyrrolopyridooxazepinones (PPOs). Compared with the lead 6 and nevirapine, several of the synthesized compounds (PBOs 13a-d and PPOs 13i-k) displayed higher inhibitory activity against wild-type RT and clinically relevant mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I, and Y188L. The most potent inhibitors were further evaluated for in vitro antiviral activity on lymphocytes and monocyte-macrophages, for cytotoxicity on a panel of cell lines, and for potential synergistic antiviral activity with AZT. Pharmacokinetic studies performed on 13b, 13c, and 13i showed that these compounds achieve high concentrations in the brain. The results of the biological and pharmacokinetic experiments suggest a potential clinical utility of analogues such as 13b-d, 13i, and 13j, in combination with nucleoside RT inhibitors, against strains of HIV-1 bearing those mutations that confer resistance to known NNRTI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / toxicity
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / pharmacology
  • Azepines / toxicity
  • Cell Line
  • Drug Design
  • Drug Synergism
  • Fluorescent Antibody Technique
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • Humans
  • Mice
  • Models, Molecular
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Reverse Transcriptase Inhibitors / toxicity
  • Structure-Activity Relationship
  • Zidovudine / pharmacology


  • Anti-HIV Agents
  • Azepines
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • HIV Reverse Transcriptase