title: Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors.
abstract: Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure-activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC(50)=0.9 microM vs. 0.54 microM, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. mario.sechi@uniss.it
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rizzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Bacchi
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.forename: Nicolino
authors.initials: N
authors.lastname: Pala
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Laleh
authors.initials: L
authors.lastname: Taheri
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C541093:6-(4-fluorobenzyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid; C541094:6-benzyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid; D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D011804:Quinolines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1