Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors.
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.
Sechi
Mario
M
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. mario.sechi@uniss.it
Rizzi
Giuseppe
G
Bacchi
Alessia
A
Carcelli
Mauro
M
Rogolino
Dominga
D
Pala
Nicolino
N
Sanchez
Tino W
TW
Taheri
Laleh
L
Dayam
Raveendra
R
Neamati
Nouri
N
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
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