Synthesis and anti-HIV-1 activity evaluation of 5-alkyl-2-alkylthio-6-(arylcarbonyl or alpha-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

J Med Chem. 2007 Apr 19;50(8):1778-86. doi: 10.1021/jm061167r. Epub 2007 Mar 24.

Abstract

A series of novel S-DABO analogues (S-DABOs, 1) were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Key structural modifications included replacement of the 6-arylmethyl group by a 6-arylcarbonyl or 6-(alpha-cyanoarylmethyl) group. Most of the compounds showed only micromolar potency against HIV-1 in MT-4 cells in vitro, though two of them (3e and 3g) were unusually potent (IC50=0.09 and 0.23 [corrected] microM, respectively) and selective (SI=1500 and 1033 [corrected] respectively). Structure-activity relationships among the newly synthesized S-DABOs are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • HIV Reverse Transcriptase / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • 2-benzoylmethylthio-6-(alpha-cyano-(1-naphthylmethyl))-3,4-dihydro-5-methylpyrimidin-4(3H)-one
  • 6-(alpha-cyanobenzyl)-3,4-dihydro-2-isopropylthio-5-methylpyrimidin-4(3H)-one
  • Anti-HIV Agents
  • Nitriles
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase