Synthesis and structure-activity relationships of C-glycosylated oxadiazoles as inhibitors of glycogen phosphorylase

A series of per-O-benzoylated 5-beta-D-glucopyranosyl-2-substituted-1,3,4-oxadiazoles was prepared by acylation of the corresponding 5-(beta-D-glucopyranosyl) tetrazole. As an alternative, oxidation of 2,6-anhydro-aldose benzoylhydrazones by iodobenzene I, I-diacetate afforded the same oxadiazoles. 1,3-Dipolar cycloaddition of nitrile oxides to per-O-benzoylated beta-D-glucopyranosyl cyanide gave the corresponding 5-beta-D-glucopyranosyl-3-substituted-1,2,4-oxadiazoles. The O-benzoyl protecting groups were removed by base-catalyzed transesterification. The 1,3,4-oxadiazoles were practically inefficient as inhibitors of rabbit muscle glycogen phosphorylase b while the 1,2,4-oxadiazoles displayed inhibitory activities in the micromolar range. The best inhibitors were the 5-beta-D-glucopyranosyl-3-(4-methylphenyl-and -2-naphthyl)- 1,2,4-oxadiazoles (K-i = 8.8 and 11.6 mu M, respectively). A detailed analysis of the structure-activity relationships is presented. (C) 2009 Elsevier Ltd. All rights reserved.