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 β-diketo acid moiety, a series of substituted indole-β-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-β-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.

Design and Synthesis of Novel Indole beta-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors / Sechi, Mario; Derudas, M; Dallocchio, R; Dess, A; Bacchi, A; Sannia, L; Carta, F; Palomba, Michele Francesco Luigi; Ragab, O; Chan, C; Shoemaker, R; Sei, S; Dayam, R; Neamati, N.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 47:(2004), pp. 5298-5310. [10.1021/jm049944f]

Design and Synthesis of Novel Indole beta-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors

SECHI, Mario;PALOMBA, Michele Francesco Luigi;
2004-01-01

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 β-diketo acid moiety, a series of substituted indole-β-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-β-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.
2004
Design and Synthesis of Novel Indole beta-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors / Sechi, Mario; Derudas, M; Dallocchio, R; Dess, A; Bacchi, A; Sannia, L; Carta, F; Palomba, Michele Francesco Luigi; Ragab, O; Chan, C; Shoemaker, R; Sei, S; Dayam, R; Neamati, N.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 47:(2004), pp. 5298-5310. [10.1021/jm049944f]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/58044
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