Synthesis of 6-(3,5-dichlorobenzyl) derivatives as isosteric analogues of the HIV drug 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil (GCA-186)

Arch Pharm (Weinheim). 2005 Jul;338(7):299-304. doi: 10.1002/ardp.200400952.

Abstract

The HIV-1 inhibitors described in this paper is closely related to 6-(3,5-dimethylbenzyl)-1-(ethoxy methyl)-5-isopropyluracil (GCA-186) an anti-HIV-1 drug that is highly active against both wild type and mutated HIV-1 strains. The two methyl groups on the 6-benzyl moiety have been shown to improve the binding stability of the drug to the NNRTI-binding site in reverse transcriptase of drug mediated mutant HIV-1 viruses. The methyl groups are replaced with isosteric chloro-atoms to avoid metabolism due to the two methyl groups. However, the isosteric chloro derivatives show tenfold less activity against HIV-1 than their corresponding methyl derivatives. The synthesis and the antiviral activities of the corresponding 1-(allyloxy- and indanyloxy)methyl-6-(3,5-dichlorobenzyl)-5-ethyluracil derivatives are also reported.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Humans
  • Isomerism
  • Microbial Sensitivity Tests / methods
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis*
  • Uracil / pharmacology

Substances

  • 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil
  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Uracil