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

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 structureactivity 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.