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Abstract
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-benzo[d][1,3]oxazin-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-benzo[d][1,3]oxazin-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.
Highlights
Diabetes mellitus, its subtype 2 (T2-DM), is considered to be a major and increasing threat to human health and accounts for an estimated more than 300 million cases of diabetes worldwide [1,2]
In continuation of the glycobiological aspects, the one-pot syntheses of novel 1,3-benzoxazine scaffold was carried out using 2-aminobenzyl alcohols and different aldehydes in chloroacetic acid via aerobic oxidative synthesis (Fig. 2)
This study demonstrated the novel synthesis of benzoxazine glycones and their effective inhibition towards glucosidases
Summary
Its subtype 2 (T2-DM), is considered to be a major and increasing threat to human health and accounts for an estimated more than 300 million cases of diabetes worldwide [1,2]. In addition to metformin as an oral drug used for the early control of T2-DM, there are a number of second- and third-line pharmacological agents available, such as sulfonylureas, thiazolidinediones, incretin-based remedies, and aglucosidase inhibitors. Given the increased perception that handling the early stages of diabetes is of crucial importance, several recent studies and approaches are focusing on agents that can delay or inhibit glucose absorption. Delaying glucose absorption, such as by blocking glycoside hydrolases ( a-glucosidases), allows extended time for b-cells to increase insulin secretion, and thereby reduce circulatory glucose levels [3,4]
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