Design, synthesis, kinetic analysis, molecular docking, and mechanistic studies of novel coumarin-oxadiazole derivatives as α-glucosidase and PTP1B inhibitors

α-Glucosidase and protein tyrosine phosphatase 1B (PTP1B) are crucial targets for diabetes treatment, and inhibiting their activity simultaneously can delay the absorption of carbohydrates and enhance insulin sensitivity by modulating the insulin signaling pathway. In this study, novel coumarin-oxadiazole derivatives were prepared by targeting these enzymes. Among them, compound 5j exhibited dual inhibitory activity against α-glucosidase and PTP1B with IC₅₀ values of 30.57 ± 0.22 μM and 7.58 ± 1.96 μM, respectively. Kinetic experiments indicated it was a mixed-type α-glucosidase inhibitor. Ultraviolet and infrared spectroscopy experiments showed it could induce conformational changes in α-glucosidase, while circular dichroism spectroscopy experiments demonstrated the ability to alter the conformations of both α-glucosidase and PTP1B. Molecular docking results revealed that the compound could embed into the active pockets of both enzymes. The sucrose-loading test showed it could reduce post-prandial blood glucose in vivo, and it had low cytotoxicity in normal cells. In conclusion, as a multi-target inhibitor, compound 5j shows great potential in the exploration and innovation of novel anti-hyperglycemic medications.