Novel alkoxy- and prenyl-xanthones derivatives as potential antidiabetic agents: Synthesis, in vitro evaluation and in silico studies

Abstract

Novel alkoxy-xanthones 5, 7, 9, 10, and 10-14 were synthesized and evaluated in vitro for their ability to inhibit α-glucosidase, α-amylase, and pancreatic lipase. Compounds 5c, 9 d, 11 d, and 14b exhibited potent α-glucosidase inhibition (IC₅₀ 20.3, 32.4, 35.2, and 18.0 µM, respectively) while showing lower activity against α-amylase compared to acarbose (IC₅₀ 308.0 µM for α-glucosidase and 25.0 µM for α-amylase). In contrast, 9b and 10c demonstrated moderate inhibition and selectivity for α-amylase. Additionally, 10a and 10c displayed mild inhibitory effects across these digestive enzymes. These results suggest that the (4-chlorophenyl)-2-oxoethoxy moiety linked to the 3-hydroxy group of xanthone core is a potent inhibitor against of α-glucosidase and has mild activity against α-amylase, whereas the allyloxy moiety shows a modest inhibitory effect. Kinetic studies indicated that compounds 9b and 11b are mixed inhibitors of α-glucosidase and non-competitive inhibitors of α-amylase. For pancreatic lipase, 10c acted as an uncompetitive inhibitor. Docking studies further supported the critical role of these hydrophobic groups in interacting with the catalytic pocket of these enzymes. ADMET studies identified derivatives 5c, 10a, 10c, and 11b as promising candidates for the developing antidiabetic agents.