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Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors

Sechi, Mario and Rizzi, Giuseppe and Bacchi, Alessia and Carcelli, Mauro and Rogolino, Dominga and Pala, Nicolino and Sanchez, Tino and Taheri, Laleh and Dayam, Raveendra and Neamati, Nouri (2009) Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors. Bioorganic & Medicinal Chemistry, Vol. 17 (7), p. 2925-2935. ISSN 0968-0896. Article.

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DOI: 10.1016/j.bmc.2008.10.088


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 (IC50 = 0.9 µM vs. 0.54 µM, 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.

Item Type:Article
ID Code:1868
Uncontrolled Keywords:HIV-1 integrase inhibitors, drug design, 4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, X-ray crystallography
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:Pergamon-Elsevier Science
Copyright Holders:© 2008 Elsevier Science
Deposited On:18 Aug 2009 10:06

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