title: 6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors.
abstract: Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck's raltegravir and Gilead's elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that show good IN inhibitory potency. This report describes the effects of introducing substituents into the 4- and 5-positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-of-magnitude and we describe several compounds that are more potent than raltegravir against the clinically relevant Y143R IN mutant.
authors.affiliation: Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States. 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: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Barry C
authors.initials: BC
authors.lastname: Johnson
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: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C580964:6,7-dihydroxy-1-oxoisoindoline-4-sulfonamide; D019428:HIV Integrase Inhibitors; D007211:Indoles; D013449:Sulfonamides; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1