Synthesis, enzyme kinetics and computational evaluation of N-(β-d-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors

Abstract

All possible isomers of N-β-d-glucopyranosyl aryl-substituted oxadiazolecarboxamides were synthesised. O-Peracetylated N-cyanocarbonyl-β-d-glucopyranosylamine was transformed into the corresponding N-glucosyl tetrazole-5-carboxamide, which upon acylation gave N-glucosyl 5-aryl-1,3,4-oxadiazole-2-carboxamides. The nitrile group of the N-cyanocarbonyl derivative was converted to amidoxime which was ring closed by acylation to N-glucosyl 5-aryl-1,2,4-oxadiazole-3-carboxamides. A one-pot reaction of protected β-d-glucopyranosylamine with oxalyl chloride and then with arenecarboxamidoximes furnished N-glucosyl 3-aryl-1,2,4-oxadiazole-5-carboxamides. Removal of the O-acetyl protecting groups by the Zemplén method produced test compounds which were evaluated as inhibitors of glycogen phosphorylase. Best inhibitors of these series were N-(β-d-glucopyranosyl) 5-(naphth-1-yl)-1,2,4-oxadiazol-3-carboxamide (Ki=30μM), N-(β-d-glucopyranosyl) 5-(naphth-2-yl)-1,3,4-oxadiazol-2-carboxamide (Ki=33μM), and N-(β-d-glucopyranosyl) 3-phenyl-1,2,4-oxadiazol-5-carboxamide (Ki=104μM). ADMET property predictions revealed these compounds to have promising oral drug-like properties without any toxicity.