Synthesis of heterocyclic N-(β-d-glucopyranosyl)carboxamides for inhibition of glycogen phosphorylase

In a DCC-mediated coupling 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylamine and propiolic acid gave N-propynoyl-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylamine which was transformed by 1,3-dipolar cycloadditions with aromatic azides and nitrile-oxides to the corresponding O-peracetylated N-(β-d-glucopyranosyl)-1-substituted-1,2,3-triazole-4-carboxamides and N-(β-d-glucopyranosyl)-3-substituted-isoxazole-5-carboxamides, respectively. These compounds were O-deacetylated by Zemplén’s protocol to be tested as inhibitors of rabbit muscle glycogen phosphorylase b. The best inhibitors of the two series were N-(β-d-glucopyranosyl)-1-(3,5-dimethyl-phenyl)-1,2,3-triazole-4-carboxamide (Ki = 34 μM) and N-(β-d-glucopyranosyl)-3-(indol-2-yl)-isoxazole-5-carboxamide (Ki = 164 μM).

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide