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

Abstract

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