Synthesis and Molecular Docking Studies of Alkoxy- and Imidazole-Substituted Xanthones as α-Amylase and α-Glucosidase Inhibitors

Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit ff-glucosidase and weakly inhibit ff-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro ff-glucosidase and ff-amylase inhibition activity. Compounds 6c, 6e, and 9b promoted higher ff-glucosidase inhibition (IC50 = 16.0, 12.8, and 4.0 mu M, respectively) and lower ff-amylase inhibition (IC50 = 76.7, 68.1, and >200 mu M, respectively) compared to acarbose (IC50 = 306.7 mu M for ff-glucosidase and 20.0 mu M for alpha-amylase). Contrarily, derivatives 10c and 10f showed higher ff-amylase inhibition (IC50 = 5.4 and 8.7 mu M, respectively) and lower ff-glucosidase inhibition (IC50 = 232.7 and 145.2 mu M, respectively). According to the structure-activity relationship, attaching 4-bromobutoxy or 40-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher ff-glucosidase inhibition and lower ff-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that 6c, 9b, and 10c are mainly mixed inhibitors on ff-glucosidase and ff-amylase. In addition, drug prediction and ADMET studies support that compounds 6c, 9b, and 10c are candidates with antidiabetic potential.