Development of new and selective Trypanosoma cruzi trans-sialidase inhibitors from sulfonamide chalcones and their derivatives.
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). IC(50) values for these inhibitors ranged from 0.6 to 7.3 microM, 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 microM, respectively, in the absence of lactose, and 4.6, 3.7 and 0.4 microM in its presence. None of the compounds tested showed any significant inhibition of the human sialidase Neu2, at concentrations up to 200 microM.
Department of Chemistry, University of British Columbia, Vancouver, BC V6T1Z1, Canada.
Jin Hyo
JH
Kim
Hyung Won
HW
Ryu
Jae Hoon
JH
Shim
Ki Hun
KH
Park
Stephen G
SG
Withers
D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
D047188:Chalcones; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D013449:Sulfonamides; C069715:trans-sialidase; D009439:Neuraminidase