title: Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors.
abstract: We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants.
authors.affiliation: Université Lille Nord de France , F-59000 Lille, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Suchaud
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bailly
authors.forename: Cedric
authors.initials: C
authors.lastname: Lion
authors.forename: Christina
authors.initials: C
authors.lastname: Calmels
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andréola
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Philippe
authors.initials: P
authors.lastname: Cotelle
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D024882:Drug Resistance, Viral; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009154:Mutation; D013329:Structure-Activity Relationship
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D019428:HIV Integrase Inhibitors; D007546:Isoquinolines; C000590783:N-(4-fluorobenzyl)-2,3-dihydroxy-7-nitro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human