Synthesis and biological evaluation of novel 2-(substituted phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs

Bioorg Med Chem. 2009 Nov 15;17(22):7749-54. doi: 10.1016/j.bmc.2009.09.035. Epub 2009 Sep 24.

Abstract

A series of novel 2-(phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones have been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC(50) ranging from 4.48microM to 0.18microM. Among them, 2-[(4-bromophenylamino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-5-methylpyrimidin-4(3H)-one 4b3 was identified as the most promising compound (EC(50) = 0.18+/-0.06microM, CC(50) >243.56microM, SI >1326). The structure-activity relationship (SAR) of these new congeners is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Drug Evaluation, Preclinical
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • HIV-1 / physiology
  • Humans
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / metabolism
  • Pyrimidinones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors