790239-15-5Relevant academic research and scientific papers
Design and synthesis of novel indole β-diketo acid derivatives as HIV-1 integrase inhibitors
Sechi, Mario,Derudas, Massimiliano,Dallocchio, Roberto,Dessì, Alessandro,Bacchi, Alessia,Sannia, Luciano,Carta, Fabrizio,Palomba, Michele,Ragab, Omar,Chan, Carney,Shoemaker, Robert,Sei, Shizuko,Dayam, Raveendra,Neamati, Nouri
, p. 5298 - 5310 (2004)
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.
