A Novel Series of Flavone-Cinnamic Acid Hybrid Derivatives as Hypoglycemic Agents: Design, Synthesis, and Activity Studies

In this work, α-glucosidase was chosen as the main therapeutic target. Novel flavone-cinnamic acid hybrid derivatives were designed, synthesized, and structurally identified based on flavone prototypes with intrinsic α-glucosidase inhibitory effects. Considering the multi-target pathological features of diabetes, α-glucosidase inhibition, Lipase inhibition, DPPH radical scavenging capacities, and insulin-resistant HepG2 cell assays were systematically evaluated to clarify their hypoglycemic mechanisms. Most acacetin-cinnamic acid hybrid derivatives exerted strong dual inhibitory effects on the two Enzymes, with 6c and 6l showing the best α-glucosidase and Lipase inhibitory activity, respectively, at the concentration of 50 µM. In the baicalein-cinnamic acid hybrid derivatives, only 7a possessed prominent Lipase inhibition, while other analogues were weak in enzyme inhibition but superior to parent baicalein. Notably, baicalein-cinnamic acid hybrid derivatives presented outstanding antioxidant activity, and significantly enhanced glucose uptake in insulin-resistant HepG2 cells, among which 7f and 7i were the most promising candidates. Enzyme inhibition and antioxidant properties jointly determined their cellular hypoglycemic effects. Overall, these hybrids exert anti-diabetic effects via synergistic multi-pathway actions, and 7f and 7i deserve further in-depth mechanistic research.