Synthesis of xanthone derivatives with extended π-systems as α-glucosidase inhibitors : Insight into the probable binding mode

Abstract A series of novel xanthone derivatives with extended π-systems, that is, benzoxanthones 2 – 4 , and their structurally perturbed analogs 5 – 9 have been designed and synthesized as α-glucosidase inhibitors. Their inhibitory activities toward yeast’s α-glucosidase were evaluated with the aim to enrich the structure–activity relationship. The results indicated that benzoxanthones 2 – 4 were capable of inhibiting in vitro yeast’s α-glucosidase 17- to 28-fold more strongly than xanthone derivative 1 that has smaller conjugated π-system. Benzoxanthone 8 , bearing angularly fused aromatic rings, and reduced benzoxanthone 5 showed decreased activities, strongly suggesting that linearly conjugated π-systems play a crucial role in the inhibition process. O-Methylation of 3-OH of benzoxanthone 2 and nitration at C4 position led to a large decrease in the activity. This indicates that 3-OH of benzoxanthone was crucial to the inhibitory activity, primarily as an H-bonding donor. The present results suggest that π–π stacking effect and H-bonding make substantial contributions to elicit the inhibitory activities of this general class of inhibitors.