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  • Title: Design and synthesis of novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors.
    Author: Sechi M, Derudas M, Dallocchio R, Dessì A, Bacchi A, Sannia L, Carta F, Palomba M, Ragab O, Chan C, Shoemaker R, Sei S, Dayam R, Neamati N.
    Journal: J Med Chem; 2004 Oct 07; 47(21):5298-310. PubMed ID: 15456274.
    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 beta-diketo acid moiety, a series of substituted indole-beta-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-beta-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.
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