Nonnucleoside HIV-1 reverse transcriptase inhibitors: Part I. Synthesis and structure-activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogues

Chem Pharm Bull (Tokyo). 2003 Jul;51(7):779-89. doi: 10.1248/cpb.51.779.

Abstract

1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues, were synthesized for evaluation as selective and potent nonnucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The anti-HIV-1 activity of these compounds was assayed in vitro using HIV-1 infected MT-4 and CEM bioassays. The EC50, CC50 and SI were recorded and calculated. The appropriate position, especially in the 1-position of the naphthyl ring, led to dramatic increases in potency, in both MT-4 and CEM cellular assays. The most important compounds in this series, 1-ethoxymethyl-5-isopropyl-6-(1-naphthylmethyl)thymine 8l (IC50=17 nM, CC50=38332 nM, SI=2229) and 1-benzyloxymethyl-5-ethyl-6-(1-naphthylmethyl)thymine 8n (IC50=17 nM, CC50=32560 nM, SI=1889) were significantly more potent than HEPT (EC50=7.0 microM, CD50=740 microM) in the anti-HIV-1 in vitro cellular assay.

MeSH terms

  • Cell Line
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Thymine / analogs & derivatives*
  • Thymine / chemical synthesis*
  • Thymine / pharmacology
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis*
  • Uracil / pharmacology

Substances

  • Reverse Transcriptase Inhibitors
  • 1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine
  • Uracil
  • HIV Reverse Transcriptase
  • Thymine