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Abstract:
A collection of xanthone-carbohydrate hybrids is reported as potential α-glucosidase inhibitors. The inhibitory activity of the xanthone core and the poly-hydroxylated commercially available drugs inspired the design of the compounds. Accordingly, both moieties were linked through a triazole core prepared by a copper-catalyzed alkyne-azide cycloaddition. After in vitro testing, compound 17f was identified as the most remarkable compound, with an IC50 of 14.9 ± 1.7 μM (acarbose had an IC50 of 7.3 ± 0.3 mM). Additionally, molecular docking studies suggested that the hybrids bind to the allosteric site, which explains the non-competitive or mixed inhibition found in enzymatic kinetics; the stability of the complex was confirmed through molecular dynamics simulation. Furthermore, an oral sucrose tolerance test (OSTT) in both healthy and diabetic mice demonstrated that benzoxanthone derivatives 17f and 18f prevent the hyperglycemic peak that occurs after sucrose administration. Although α-glucosidase inhibition is a key mechanism of action for xanthone 17f, it also improved plasma glucose levels after 60 min of sucrose administration in diabetic mice, resulting in a decrease of 42 % compared to initial glucose levels and showing better reduction than acarbose (reduction of 22 %), suggesting a complementary antidiabetic effect.

Keywords:
T2DM, Xanthone, Triazole, Carbohydrates, α-glucosidase inhibitors