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Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives of carbohydrates as alpha-glucosidases inhibitors.

Abstract：

:A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-D-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Ferreira SB,Sodero AC,Cardoso MF,Lima ES,Kaiser CR,Silva FP,Ferreira VF

doi

10.1021/jm901265h

subject

Has Abstract

pub_date

2010-03-25 00:00:00

pages

2364-75

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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