6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2400-2. doi: 10.1016/j.bmcl.2011.02.069. Epub 2011 Feb 18.

Abstract

N-3-hydroxylation of pyrimidine-2,4-diones was recently found to yield inhibitors of both HIV-1 reverse transcriptase (RT) and integrase (IN). An extended series of analogues featuring a benzoyl group at the C-6 position of the pyrimidine ring was synthesized. Through biochemical studies it was found that these new analogues are dually active against both RT and IN in low micromolar range. Antiviral assays confirmed that these new inhibitors are active against HIV-1 in cell culture at nanomolar to low micromolar range, further validating 3-hydroxypyrimidine-2,4-diones as a viable scaffold for antiviral development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • HIV Integrase / chemistry*
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • HIV Integrase Inhibitors
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • HIV Integrase
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • pyrimidine