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Bioorg Med Chem ; 25(21): 6049-6059, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29032929

RESUMO

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-ßGalOMe. 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.


Assuntos
Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Galectina 3/metabolismo , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fibroblastos/parasitologia , Galactose/química , Galactose/farmacologia , Galectinas , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Haplorrinos , Humanos , Estrutura Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia
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