Thiadiazole based β-carboline derivatives as potential α-glucosidase inhibitors: design, synthesis, and bioactivity...

α-Glucosidase has always been one essential target for clinical prevention and treatment of diabetes. To develop effective α-glucosidase inhibitors, twenty-seven thiadiazole based β-carboline derivatives (TC1-TC27) were designed and synthesized by pharmacophore hybridization strategy, and systematically evaluated their inhibitory activity and binding characteristics against α-glucosidase. All synthesized derivatives (TC1-TC27) displayed significant inhibitory activity against α-glucosidase, with TC16 emerging as the most potent compound (IC₅₀ = 2.62 ± 0.21 μM), far surpassing the reference inhibitor acarbose (IC₅₀ = 210.75 ± 9.52 μM). Furthermore, fluorescence spectra and CD spectra results illustrated the binding of TC16 onto α-glucosidase, which caused the enzyme conformation transition to induce activity decrease. Finally, molecular docking elucidated hydrogen bonds and hydrophobic interactions kept the binding of TC16 onto α-glucosidase. In summary, this work provides a class of thiadiazole based β-carboline derivatives as potential α-glucosidase inhibitors.