title: 2-hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4.
abstract: We report herein the synthesis of a series of fifteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives. Alkyl and arylalkyl groups were introduced on position 4 of the basis scaffold. All the compounds presented poor inhibitory properties against HIV-1 reverse transcriptase ribonuclease H (RNase H). Four compounds inhibited HIV-1 integrase at a low micromolar level. A docking study using the later crystallographic data available for PFV integrase allowed us to explain the slightly improved integrase inhibitory activities of 4-pentyl and 4-(3-phenylpropyl)-2-hydroxyisoquinoline-1,3(2H,4H)-diones, when compared to the basis scaffold. Physicochemical studies were consistent with 1:1 and 1:2 (metal/ligand) stoichiometries of the magnesium complexes in solution. Unfortunately all tested compounds exhibited high cellular cytotoxicity in cell culture which limited their applications as antiviral agents. However these identified integrase inhibitors provide a very good basis for the development of new hits.
authors.affiliation: Université Lille Nord de France, F-59000 Lille, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Billamboz
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bailly
authors.forename: Cédric
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: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.forename: Philippe
authors.initials: P
authors.lastname: Cotelle
mesh_terms: D000478:Alkylation; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C558516:2-hydroxyisoquinoline-1,3(2H,4H)-dione; D019428:HIV Integrase Inhibitors; D007546:Isoquinolines; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase