Hybrid diarylbenzopyrimidine non-nucleoside reverse transcriptase inhibitors as promising new leads for improved anti-HIV-1 chemotherapy

Bioorg Med Chem. 2010 Jul 15;18(14):5039-47. doi: 10.1016/j.bmc.2010.05.081. Epub 2010 Jun 4.

Abstract

Molecular hybridization of the known anti-HIV-1 template DPC083 and etravirine based on docking model overlay has been generated a novel series of diarylbenzopyrimidine analogues (DABPs) (5a-z). These new hybrids were assessed for their activity against HIV in MT-4 cell cultures. Most of these compounds showed good activity against wild-type HIV-1 and mutant viruses. In particular, compound 5r showed the most potent activity against wild-type HIV-1 with an EC50 value of 1.8 nM, and with a selectivity index up to 111,954. It also proved more active against mutant L100I, K103N, Y188L, and K103N+Y181C RT HIV-1 strains than efavirenz.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • HIV Infections / drug therapy*
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1 / drug effects*
  • Humans
  • Models, Molecular
  • Nitriles
  • Protein Binding
  • Pyridazines / chemistry
  • Pyridazines / pharmacology
  • Pyrimidines
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • DPC 083
  • Nitriles
  • Pyridazines
  • Pyrimidines
  • Quinazolines
  • Reverse Transcriptase Inhibitors
  • etravirine
  • HIV Reverse Transcriptase