title: Novel benzoxazine-based aglycones block glucose uptake in vivo by inhibiting glycosidases.
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.
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India.
authors.forename: Hanumantharayappa
authors.initials: H
authors.lastname: Bharathkumar
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, India.
authors.forename: Mahalingam S
authors.initials: MS
authors.lastname: Sundaram
authors.affiliation: Department of Chemistry, University of Mysore, Manasagangotri, Mysore, India.
authors.forename: Swamy
authors.initials: S
authors.lastname: Jagadish
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Shardul
authors.initials: S
authors.lastname: Paricharak
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, India.
authors.forename: Mahadevappa
authors.initials: M
authors.lastname: Hemshekhar
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mason
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, India.
authors.forename: Kempaiah
authors.initials: K
authors.lastname: Kemparaju
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, India.
authors.forename: Kesturu S
authors.initials: KS
authors.lastname: Girish
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India.
authors.lastname: Basappa
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Department of Chemistry, University of Mysore, Manasagangotri, Mysore, India.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity
chemical_list: D006026:Glycoside Hydrolases; D005947:Glucose