Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles and evaluation as glycogen phosphorylase inhibitors

• Glycogen phosphorylase is a target enzyme for the regulation of glycemia in the context of type 2 diabetes.
• Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles was achieved from the condensation of glucosyl azide and Boc-protected propargyl amine.
• Inhibition of GP was in the high micromolar range for the designed inhibitors.
• The Boc-carbamate group could be identified as a potential pharmacophore for the inhibition of GP.

Glycogen phosphorylase (GP) appears as a key enzyme for the control of hyperglycemia in the context of type 2 diabetes. In order to gain additional data for structure–activity studies of the inhibition of this enzyme, a series of eight GP inhibitor candidates were prepared from peracetylglucopyranosyl azide 1 by click-chemistry. The need for a N-Boc-protected propargylamine was identified in the CuAAC with azide 1 under Meldal’s conditions, while Sharpless’ conditions were better adapted to the CuAAC of azide 1 with propargyl bromide. Cycloaddition of Boc-propargylamine with azide 1 afforded the N-Boc precursor of a 4-aminomethyl-1-glucosyl-1,2,3-triazole which gave access to a series of eight amide and sulfonamide derivatives. After deacetylation, enzymatic studies revealed poor to moderate inhibitions toward this enzyme. The N-Boc-protected amine was the best inhibitor (IC50 = 620 μM) unexpectedly slightly better than the 2-naphthylamido substituted analogue (IC50 = 650 μM).

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