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 lM vs. 0.54 lM, 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.

Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors / MARIO SECHI; GIUSEPPE RIZZI; ALESSIA BACCHI; MAURO CARCELLI; DOMINGA ROGOLINO; NICOLINO PALA; TINO W. SANCHEZ C; LALEH TAHERI; RAVEENDRA DAYAM; NOURI NEAMATI. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 17:(2009), pp. 2925-2935.

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

SECHI, Mario;
2009

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 (IC50 = 0.9 lM vs. 0.54 lM, 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/86732
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