Galactosyl and sialyl clusters: synthesis and evaluation against T. cruzi parasite
AbstractThe multivalent effect of carbohydrates (glycoclusters) has been explored to study important biological targets and processes involvingTrypanosoma cruzi(T. cruzi) infection. Likewise, CuAAC cycloaddition reactions (click chemistry) have been applied as useful strategy in the discovery of bioactive molecules. Hence, we describe the synthesis of 1,2,3-triazole-based tetravalent homoglycoclusters (1–3) and heteroglycoclusters (4and5) ofd-galactopyranose (C-1 and C-6 positions) and sialic acid (C-2 position) to assess their potential to inhibitT. cruzicell invasion and also its cell surfacetrans-sialidase (TcTS). The target compounds were synthesised in good yields (52–75 %)viaclick chemistry by coupling azidosugars galactopyranose and sialic acid with alkynylated pentaerythritol or tris(hydroxymethyl)-aminomethane (TRIS) scaffolds.T. cruzicell invasion inhibition assays showed expressive low parasite infection index values (5.3–6.8) for most compounds. However, most glycoclusters proved to be weak TcTS inhibitors at 1 mM (<17 %), except the tetravalent sialic acid3(99 % at 1 mM, IC50450 μM). Therefore, we assume thatT. cruzicell invasion blockage is not due to TcTS inhibition by itself, but rather by other mechanisms involved in this process. In addition, all glycoclusters were not cytotoxic and had significant trypanocidal activity upon parasite survival of amastigote forms.
