http://www.cnr.it/ontology/cnr/individuo/prodotto/ID15101

Design and Synthesis of Novel Indole b-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors (Articolo in rivista)

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Design and Synthesis of Novel Indole b-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors (Articolo in rivista) (literal)

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Alternative label

M. Sechi, M. Derudas, R. Dallocchio, A. Dessì, A. Bacchi, L. Sannia, F. Carta, M. Palomba, O. Ragab, C. Chan, R. Shoemaker, S. Sei, R. Dayam and N. Neamati (2004)
Design and Synthesis of Novel Indole b-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors
in Journal of medicinal chemistry; ACS, American chemical society, Washington, DC (Stati Uniti d'America)
(literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

M. Sechi, M. Derudas, R. Dallocchio, A. Dessì, A. Bacchi, L. Sannia, F. Carta, M. Palomba, O. Ragab, C. Chan, R. Shoemaker, S. Sei, R. Dayam and N. Neamati (literal)

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Università di Sassari, Università di Parma, University of Southern California, CNR (literal)

Titolo

Design and Synthesis of Novel Indole b-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors (literal)

Abstract

Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure-activity relationship among the substituted indole nucleus bearing a ?-diketo acid moiety, a series of substituted indole-?-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-?-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN. (literal)

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