Development of New and Selective Trypanosoma cruzi trans-Sialidase Inhibitors from Sulfonamide Chalcones and Their Derivatives

摘要

A series of sulfonamide-containing hydroxylated chalcone (4-7) and quinolinone (8, 9) derivatives was synthesised and tested for inhibition of the trans-sialidase from Trypanosoma cruzi (TcTS). IC50 values for these inhibitors ranged from 0.6 to 7.3 mu m, with the dihydroxylated (catechol) derivatives being the tightest binders. Full kinetic analyses of inhibition were performed for these catechol derivatives, both for the transglycosylation reaction in the presence of lactose and for the hydrolysis reaction in its absence. Competitive inhibition was seen in each case with K-i values for 5, 7 and 9 of 2.0, 2.2 and 0.2 mu M, respectively, in the absence of lactose, and 4.6, 3.7 and 0.4 mu M in its presence. None of the compounds tested showed any significant inhibition of the human sialidase Neu2, at concentrations up to 200 mu M.