Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors

Bioorg Med Chem Lett. 2011 May 15;21(10):2986-90. doi: 10.1016/j.bmcl.2011.03.047. Epub 2011 Mar 21.

Abstract

New tricyclic HIV-1 integrase (IN) inhibitors were prepared that combined structural features of bicyclic pyrimidinones with recently disclosed 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. This combination resulted in the introduction of a nitrogen into the aryl ring and the addition of a fused third ring to our previously described inhibitors. The resulting analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays, with good selectivity for strand transfer relative to 3'-processing.

Publication types

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

MeSH terms

  • Biological Assay
  • Cells, Cultured
  • Cyclization
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis*
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Hydroxylation
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Structure-Activity Relationship

Substances

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