N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase

Bioorg Med Chem. 2013 Mar 1;21(5):1150-8. doi: 10.1016/j.bmc.2012.12.027. Epub 2013 Jan 3.

Abstract

A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC(50)=0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • Cinnamates / chemistry
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Molecular Docking Simulation
  • Mutation
  • Protein Structure, Tertiary
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis
  • Uracil / pharmacology

Substances

  • Cinnamates
  • Reverse Transcriptase Inhibitors
  • Uracil
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase