Synthesis, anti-α-glucosidase activity, inhibition interaction, and anti-diabetic activity of novel cryptolepine derivatives

To find potential α-glucosidase inhibitors, thirty-seven cryptolepine derivatives (FM1 ∼ 37) were designed and synthesized. Compared to parent compound cryptolepine (IC50 = 440.12 ± 50.04 μM) and positive compound acarbose (IC50 = 523.42 ± 42.15 μM), all synthesized compounds showed stronger α-glucosidase inhibitory activities with IC50 values of 6.45 ± 0.68 ∼ 48.03 ± 2.18 μM. The strongest compound FM25 (IC50 = 6.45 ± 0.68 μM) was proved to be a mixed-type inhibitor with Ki value of 0.18 μM. Fluorescence quenching results clarified that the binding of FM25 with α-glucosidase quenched the fluorescence of α-glucosidase in a static process. CD spectra, 3D spectra, and docking results indicated that the binding of FM25 with α-glucosidase led to the conformation change of α-glucosidase to reduce enzyme activity. In vivo experiments showed FM25 could reduce the fasting blood glucose and improve glucose tolerance and hypertension in STZ-induced diabetes mice.