title: Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture.
abstract: Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.
authors.affiliation: Unité de Chimie Organique, UPRES-A du CNRS 8076, Centre d'Etudes Pharmaceutiques, Université Paris-Sud, 5 rue J.-B. Clément, 92296 Châtenay-Malabry, France.
authors.forename: F
authors.initials: F
authors.lastname: Zouhiri
authors.forename: J F
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: K
authors.initials: K
authors.lastname: Mekouar
authors.forename: D
authors.initials: D
authors.lastname: Desmaële
authors.forename: D
authors.initials: D
authors.lastname: Savouré
authors.forename: H
authors.initials: H
authors.lastname: Leh
authors.forename: F
authors.initials: F
authors.lastname: Subra
authors.forename: M
authors.initials: M
authors.lastname: Le Bret
authors.forename: C
authors.initials: C
authors.lastname: Auclair
authors.forename: J
authors.initials: J
authors.lastname: d'Angelo
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011804:Quinolines; D013343:Styrenes; D019427:HIV Integrase