Toward potent α-glucosidase inhibitors based on xanthones: A closer look into the structure–activity correlations

A series of novel xanthone derivatives 6–16 having non-coplanar and flexible structures were synthesized as potent α-glucosidase inhibitors. Biological evaluation indicated that compounds 6–12 bearing one or two naphthol moieties exhibited up to 30-fold enhanced activities compared with their corresponding parent compounds 2–5, whereas compounds 13–16 bearing one dihydroxylnaphthalenyl group showed decreased activities compared with their corresponding analogs 6–9 having one naphthol group. Among them, compounds 7–8, 10–12 and 15 were more active than 1-deoxynojirimycin, a well-known inhibitor for α-glucosidase. The structure–activity correlations suggested that inhibiting of α-glucosidase was a result of multiple interactions with the enzyme, including π-stacking, hydrophobic effect and conformational flexibility due to the structural non-coplanarity. In addition, compounds 4, 8 and 15 showed non-competitive inhibition.

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► Non-coplanar and flexible xanthone derivatives were synthesized in 25–50%.
► The inhibitory activities against yeast’s α-glucosidase were up to 30-fold enhanced.
► π-Stacking, hydrophobic effect and conformational flexibility were found to be predominant factors for modulating the activity.
► Compounds 4, 8 and 15 were found to act as non-competitive inhibitors.