Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 18, Pages 5738-5747Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.07.024
Keywords
1,2,4-Oxadiazole; 1,3,4-Oxadiazole; beta-d-Glucopyranosyl derivatives; Glycogen phosphorylase; Inhibitor; ADMET
Funding
- Hungarian Scientific Research Fund [OTKA CK77712, CNK80709]
- European Social Fund [TAMOP-4.2.2.-08/1/2008-0014, TAMOP 4.2.1./B-09/1/KONV-2010-0007, TAMOP-4.2.2./B-10/1-2010-0024]
- TAMOP [4.2.4.A/2-11-12012-0001]
- Hungarian Academy of Sciences
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All possible isomers of N-beta-D-glucopyranosyl aryl-substituted oxadiazolecarboxamides were synthesised. O-Peracetylated N-cyanocarbonyl-beta-D-glucopyranosylamine was transformed into the corresponding N-glucosyl tetrazole-5-carboxamide, which upon acylation gave N-glucosyl 5-ary1-1,3,4-oxadiazole-2-carboxamides. The nitrite 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 beta-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 Zemplen Method produced test compounds which were evaluated as inhibitors of glycogen phosphorylase. Best inhibitors of these series were N-(beta-D-glucopyranosyl) 5-(naphth-1-yl)-1,2,4-oxadiazol-3-carboxamide (K-i = 30 mu M), N-(beta-D-glucopyranosyl) 5-(naphth-2-y1)-1,3,4-oxadiazol-2-carboxamide (K-i= 33 mu M), and N-(beta-D-glucopyranosyl) 3-phenyl-1,2,4-oxadiazol-5-carboxamide (K-i= 104 mu M). ADMET property predictions revealed these compounds to have promising oral drug-like properties without any toxicity. (C) 2013 Elsevier Ltd. All rights reserved.
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