Galactosyl and sialyl clusters: Synthesis and evaluation against T. cruzi parasite

Abstract

The multivalent effect of carbohydrates (glycoclusters) has been explored to study important biological targets and processes involving Trypanosoma 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 (4 and 5) of d-galactopyranose (C-1 and C-6 positions) and sialic acid (C-2 position) to assess their potential to inhibit T. cruzi cell invasion and also its cell surface trans-sialidase (TcTS). The target compounds were synthesised in good yields (52-75 %) via click chemistry by coupling azidosugars galactopyranose and sialic acid with alkynylated pentaerythritol or tris(hydroxymethyl)-aminomethane (TRIS) scaffolds. T. cruzi cell 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 acid 3 (99 % at 1 mM, IC50 450 μM). Therefore, we assume that T. cruzi cell 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.