Novel benzoxazine-based aglycones block glucose uptake in vivo by inhibiting glycosidases

Bharathkumar, H. and Sundaram, M. S. and Jagadish, S. and Paricharak, S. and Hemshekhar, M. and Mason, D. and Kemparaju, K. and Girish, K. S. and Basappa and Bender, A. and Rangappa, K. S. (2014) Novel benzoxazine-based aglycones block glucose uptake in vivo by inhibiting glycosidases. PLoS ONE, 9 (7). ISSN 1932-6203

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Glycoside hydrolases catalyze the selective hydrolysis of glycosidic bonds in oligosaccharides, polysaccharides, and their conjugates. β-glucosidases occur in all domains of living organisms and constitute a major group among glycoside hydrolases. On the other hand, the benzoxazinoids occur in living systems and act as stable β-glucosides, such as 2-(2,4-dihydroxy-7-methoxy- 2H-1,4-benzoxazin-3(4H)-one)-β-D-gluco-pyranose, which hydrolyse to an aglycone DIMBOA. Here, we synthesized the library of novel 1,3-benzoxazine scaffold based aglycones by using 2-aminobenzyl alcohols and aldehydes from one-pot reaction in a chloroacetic acid catalytic system via aerobic oxidative synthesis. Among the synthesized benzoxazines, 4-(7-chloro-2,4-dihydro-1H- benzod1,3oxazin-2-yl)phenol (compound 7) exhibit significant inhibition towards glucosidase compared to acarbose, with a IC50 value of 11.5 μM. Based upon results generated by in silico target prediction algorithms (Naïve Bayesian classifier), these aglycones potentially target the additional sodium/glucose cotransporter 1 (where a log likelihood score of 2.70 was observed). Furthermore, the in vitro glucosidase activity was correlated with the in silico docking results, with a high docking score for the aglycones towards the substrate binding site of glycosidase. Evidently, the in vitro and in vivo experiments clearly suggest an anti-hyperglycemic effect via glucose uptake inhibition by 4-(7-chloro-2,4-dihydro-1H-benzod1,3oxazin-2-yl)phenol in the starved rat model. These synthetic aglycones could constitute a novel pharmacological approach for the treatment, or re-enforcement of existing treatments, of type 2 diabetes and associated secondary complications. © 2014 Bharathkumar et al.

Item Type: Article
Uncontrolled Keywords: animal experiment, controlled study, drug synthesis, in vitro study, nonhuman, unclassified drug, animal, Animals, adult, animal tissue, rat, Rats, metabolism, molecular docking, glucose, 4 (2, drug efficacy, amylase, enzyme inhibition, article, antidiabetic activity, glucose transport, Bayes theorem, Diabetes Mellitus, non insulin dependent diabetes mellitus, Type 2, drug binding, drug dose comparison, IC 50, maltose, Glucose, glycosidase, sucrose, binding site, enzyme specificity, Substrate Specificity, Bayes Theorem, alpha glucosidase, acarbose, Binding Sites, 3]oxazine, 2 (1h indol 3 yl) 2, 2 (2 butyl 4 chloro 1h imidazol 5 yl) 2, 2 (2 methyl 1h indol 3 yl) 2, 3 (2, 3 (6 chloro 2, 3 (6 methyl 2, 3]oxazin 2 yl) 4h chromen 4 one, 3]oxazin 2 yl)phenol, 4 (7 chloro 2, 4 dihydro 1h benzod1, 6 chloro 2 (2 phenyl 1h indol 3 yl) 2, 6 methyl 2 (2 methyl 1h indol 3 yl) 2, 6 methyl 2 (2 phenyl 1h indol 3 yl) 2, 7 chloro 2 (1h indol 3 yl) 2, aglycone, benzoxazine derivative, classifier, Glycoside Hydrolases, sodium glucose cotransporter 1, swine
Subjects: C Chemical Science > Chemistry
Divisions: Department of > Chemistry
Depositing User: Arshiya Kousar Library Assistant
Date Deposited: 15 Jun 2019 10:06
Last Modified: 15 Jun 2019 10:06

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