Inhibitory Activity Evaluation And Synthesis Of Tetracyclic Oxindole Derivatives As ?-glucosidase Inhibitors

The ?-glucosidase inhibitors (AGIs) are the clinically preferred oral drugs for the treatment of type II diabetes and an adjunct to the treatment of type I diabetes, targeting a-glucosidase. Clinical AGIs are "pseudo-sugar" with flatulence and other side effects.Therefore, the discovery of new AGIs is of great significance. The synthesis and activity studies of tetracyclic oxindole alkaloids have attracted more and more attention in the past few decades.On the basis of preliminary research of our group, three series of novel tetracyclic oxindole derivatives were synthesized via tandem Suzuki coupling-Michael addition reaction catalyzed by palladium. Twenty three new derivatives were designed and synthesized. The structure of all key intermediates and target compounds have been confirmed by 1H-NMR, 13C-NMR and LC/MS.These compounds were evaluated for a-glucosidase inhibitory activity in vitro.Compound 5p exhibited the most potent inhibitory activity with IC50 0.7 ?M and was about 170 times as active as acarbose (IC50 = 115.8 ?M). Structure-activity relationship studies suggested that the substitution of N-1 with 4-trifluoromethylbenzyl was more favorable to improve the activity. The 3-carbonyl group was a essential group. 5-O series of derivatives were more active than the 5-N counterparts. Besides, R3 group played an important role in the a-glucosidase inhibitory activity, especially with benzidine, at the R3 position can efficiently increase the inhibitory activity. Enzyme kinetic study suggested that compound 5p inhibit the ?-glucosidase by irreversible and mixed competitive way. Fluorescence spectra results indicated that 5p directly bound to a-glucosidase. In addition, Molecular docking study showed that 5p has a high binding affinity with a-glucosidase due to the presence of hydrogen bonding, van der Waals, Pi and Sigma-Pi interactions, as well as matching ability with the active pocket. Cell level glucose consumption experiments showed that compound 5p was effective in promoting glucose consumption and further confirmed the antidiabetic effect. In this study, the above results demonstrated that compound 5p could be a potential a-glucosidase inhibitor and deserved further research,which laid basic foundation for the discovery of new a-glucosidase inhibitory drugs.