title: Synthesis of substituted 2-(β-D-glucopyranosyl)-benzimidazoles and their evaluation as inhibitors of glycogen phosphorylase.
abstract: 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=2.8μM) and 2-(β-d-glucopyranosyl)-naphtho[2,3-d]imidazole (Ki=2.1μM) exhibiting a ∼3-4 times stronger binding than the unsubstituted parent compound.
authors: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary.
authors: Éva
authors: É
authors: Bokor
authors: Enikő
authors: E
authors: Szilágyi
authors: Tibor
authors: T
authors: Docsa
authors: Pál
authors: P
authors: Gergely
authors: László
authors: L
authors: Somsák
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000201:enzymology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D024982:Glycogen Phosphorylase, Muscle Form
keywords: 2-C-Glycopyranosyl benzimidazole; C-Glycopyranosyl-formimidate; C-Glycopyranosyl-thioformimidate; Glycogen phosphorylase; Inhibitor