Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case

Per-O-acetylated beta-D-glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe3 which was then acylated to N-acyl-beta-D-glucopyranosylamines. The same azide and substituted acetylenes gave 1-(beta-D-glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide-alkyne cycloadditions. Deprotection of these products by the Zemplen method furnished beta-D-Glc(p)-NHCO-R derivatives as well as 1-(beta-D-Glc(p))-4-R-1,2,3-triazoles which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides versus triazoles with the same R group displayed similar inhibition constants. X-ray crystallographic studies on the enzyme-inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compounds a different orientation of the aromatic part and changes in the conformation of the 280s loop were observed. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided. (C) 2009 Elsevier Ltd. All rights reserved.