Binding of triazole-linked galactosyl arylsulfonamides to galectin-3 affects Trypanosoma cruzi cell invasion

Publication date: Available online 30 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Marcelo Fiori Marchiori, Thalita B. Riul, Leandro Oliveira Bortot, Peterson Andrade, Getúlio G. Junqueira, Giuseppina Foca, Nunzianna Doti, Menotti Ruvo, Marcelo Dias-Baruffi, Ivone Carvalho, Vanessa Leiria Campo
The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides 1-7 as potential inhibitors of Trypanosoma cruzi cell invasion is described. These target compounds were synthesized by Cu(I)-catalysed azide-alkyne cycloaddition reaction ('click chemistry') between different azide arylsulfonamides and the alkyne-based sugar 3-O-propynyl-βGalOMe. Inhibition assays of T. cruzi cell invasion with compounds 1-7 showed reduced values of infection index (∼20) for compounds 3 and 5, bearing the corresponding 5-methylisoxazole and 2,4-dimethoxypyrimidine groups, which also presented higher binding affinities to galectin-3 (EC50 17-18 μM) in Corning Epic label-free assays. In agreement with experimental results, the assessment of the theoretical binding of compounds 1-7 to galectin-3 by MM/PBSA method displayed higher affinities for compounds 3 (-9.7 Kcal/ mol) and 5 (-11.1 Kcal/ mol). Overall, these achievements highlight compounds 3 and 5 as potential T. cruzi cell invasion blockers by means of a galectin-3 binding-related mechanism, revealing galectin-3 as an important host target for design of novel anti-trypanosomal agents.

Graphical abstract

http://ift.tt/2yPoXEW