Synthesis of α- and β-d-glucopyranosyl triazoles by CuAAC ‘click chemistry’: reactant tolerance, reaction rate, product structure and glucosidase inhibitory properties

CuI-catalysed azide alkyne 1,3-dipolar cycloaddition (CuAAC) ‘click chemistry’ was used to assemble a library of 21 α-d- and β-d-glucopyranosyl triazoles, which were assessed as potential glycosidase inhibitors. In the course of this work, different reactivities of isomeric α- and β-glucopyranosyl azides under CuAAC conditions were noted. This difference was further investigated using competition reactions and rationalised on the basis of X-ray crystallographic data, which revealed significant differences in bond lengths within the azido groups of the α- and β-anomers. Structural studies also revealed a preference for perpendicular orientation of the sugar and triazole rings in both the α- and β-glucosyl triazoles in the solid state. The triazole library was assayed for inhibition of sweet almond β-glucosidase (GH1) and yeast α-glucosidase (GH13), which led to the identification of a set of glucosidase inhibitors effective in the 100 μM range. The preference for inhibition of one enzyme over the other proved to be dependent on the anomeric configuration of the inhibitor, as expected.

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