Synthesis, enzyme kinetics and computational evaluation of N-(β-D-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors.
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 = 30 μM), N-(β-D-glucopyranosyl) 5-(naphth-2-yl)-1,3,4-oxadiazol-2-carboxamide (Ki =33 μM), and N-(β-D-glucopyranosyl) 3-phenyl-1,2,4-oxadiazol-5-carboxamide (Ki = 104 μM). ADMET property predictions revealed these compounds to have promising oral drug-like properties without any toxicity.
Department of Organic Chemistry, University of Debrecen, Hungary.
Mária
M
Polyák
Gergely
G
Varga
Bence
B
Szilágyi
László
L
Juhász
Tibor
T
Docsa
Pál
P
Gergely
Jaida
J
Begum
Joseph M
JM
Hayes
László
L
Somsák
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010069:Oxadiazoles / Q000737:chemistry*; D011817:Rabbits; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D009005:Monosaccharides; C587139:N-(beta-D-glucopyranosyl)3-phenyl-1,2,4-oxadiazol-5-carboxamide; C587138:N-(beta-D-glucopyranosyl)5-(naphth-1-yl)-1,2,4-oxadiazol-3-carboxamide; D010069:Oxadiazoles; D024981:Glycogen Phosphorylase
1,2,4-Oxadiazole; 1,3,4-Oxadiazole; ADMET; Glycogen phosphorylase; Inhibitor; β-d-Glucopyranosyl derivatives