Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs

Bioorg Med Chem. 2011 Sep 1;19(17):5117-24. doi: 10.1016/j.bmc.2011.07.023. Epub 2011 Jul 26.

Abstract

A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 μM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 μM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / toxicity
  • Cell Line
  • Chlorine / chemistry
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / enzymology*
  • Humans
  • Mutation
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / toxicity
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / toxicity
  • Structure-Activity Relationship

Substances

  • 4-((4-((2-chlorophenyl)(hydroxy)methyl)pyrimidin-2-yl)amino)benzonitrile
  • Aniline Compounds
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Chlorine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase