Design, synthesis, and SAR of naphthyl-substituted Diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase

ChemMedChem. 2009 Sep;4(9):1537-45. doi: 10.1002/cmdc.200900212.

Abstract

A series of 38 2-naphthyl-substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild-type HIV-1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild-type HIV-1 with an EC50 value of 0.002 microM and against the double mutant strain with an EC50 value of 0.24 microM; the selectivity index (SI) against wild-type is >180 000, the highest SI value among DAPY analogues. The structure-activity relationship (SAR) of the newly synthesized DAPYs is presented herein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / toxicity
  • Binding Sites
  • Cell Line
  • Computer Simulation
  • Drug Design
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / toxicity
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / toxicity
  • Structure-Activity Relationship

Substances

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