Synthesis of substituted 2-(β-d-glucopyranosyl)-benzimidazoles and their evaluation as inhibitors of glycogen phosphorylase

Microwave assisted condensation of O-perbenzoylated C-(β-d-glucopyranosyl)formic acid with 1,2-diaminobenzenes in the presence of triphenylphosphite gave the corresponding O-protected 2-(β-d-glucopyranosyl)-benzimidazoles in moderate yields. O-Perbenzoylated C-(β-d-glucopyranosyl)formamide and -thioformamide were transformed into the corresponding ethyl C-(β-d-glucopyranosyl)formimidate and -thioformimidate, respectively, by Et3O·BF4. Treatment of the formimidate with 1,2-diaminobenzenes afforded O-protected 2-(β-d-glucopyranosyl)-benzimidazoles in good to excellent yields. Similar reaction of the thioformimidate gave these compounds in lower yields. The O-benzoyl protecting groups were removed by the Zemplén protocol. These test compounds were assayed against rabbit muscle glycogen phosphorylase (GP) b, the prototype of liver GP, the rate limiting enzyme of glycogen degradation. The best inhibitors were 2-(β-d-glucopyranosyl)-4-methyl-benzimidazole (Ki = 2.8 μM) and 2-(β-d-glucopyranosyl)-naphtho[2,3-d]imidazole (Ki = 2.1 μM) exhibiting a ∼3–4 times stronger binding than the unsubstituted parent compound.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of C-(β-d-glucopyranosyl)formimidates and -thioformimidates. ► New synthesis of C-(β-d-glucopyranosyl)-benzimidazoles. ► Low micromolar inhibitors of glycogen phosphorylase.