title: Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors.
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.
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, USA. xuezhi.zhao@nih.gov
authors.forename: Xue Zhi
authors.initials: XZ
authors.lastname: Zhao
authors.forename: Kasthuraiah
authors.initials: K
authors.lastname: Maddali
authors.forename: Mathieu
authors.initials: M
authors.lastname: Metifiot
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.forename: B Christie
authors.initials: BC
authors.lastname: Vu
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D001681:Biological Assay; D002478:Cells, Cultured; D003500:Cyclization; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D011744:Pyrimidinones; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1