Structural modifications of 5,6-dihydroxypyrimidines with anti-HIV activity

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7114-8. doi: 10.1016/j.bmcl.2012.09.070. Epub 2012 Oct 2.

Abstract

A series of 5,6-dihydroxypyrimidine analogs were synthesized and evaluated for their anti-HIV activity in vitro. Among all of the analogs, several compounds exhibited significant anti-HIV activity, especially 1b and 1e, which showed the most potent anti-HIV activity with EC(50) values of 0.14 and 0.15 μM, and TI (therapeutic index) values of >300 and >900, respectively. Further docking studies revealed that the representative compounds 1e and 3a could meet the HIV-1 integrase inhibition minimal requirements of a chelating domain (two metal ions) and an aromatic domain (π-π stacking interactions).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • HIV Integrase / chemistry*
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / toxicity
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / toxicity
  • Structure-Activity Relationship

Substances

  • HIV Integrase Inhibitors
  • Pyrimidines
  • HIV Integrase
  • pyrimidine
  • p31 integrase protein, Human immunodeficiency virus 1