Identification of 1,3,4-oxadiazolyl-containing -carboline derivatives as novel -glucosidase inhibitors with antidiabetic activity

In this study, we designed and synthesized a novel class of 1,3,4-oxadiazolyl-containing beta-carboline derivatives, i. e., compounds f1 -f35 as potential alpha-glucosidase inhibitors. All the synthesized compounds possessed outstanding alpha-glucosidase inhibitory activity with the IC50 values in the range of 3.07-15.49 mu M, representing that they are 36-183-fold more active than a positive control, acarbose (IC50 = 564.28 mu M). Among them, compound f26 exhibited the highest alpha-glucosidase inhibitory activity (IC50 = 3.07 mu M) and was demonstrated to function as a reversible and noncompetitive inhibitor. Mechanistic studies by means of 3D fluorescence spectra, CD spectra and molecular docking suggested that complexation of compound f26 with alpha-glucosidase through hydrogen bonds and hydrophobic interactions, led to changes in the conformation and secondary strictures of alpha-glucosidase and further the inhibition of the enzymatic activity. In vivo results showed that oral administration of compound f26 (50 mg/kg/day) could obviously reduce the levels of fasting blood glucose and improve glucose tolerance and dyslipidemia in diabetic mice. The present findings suggest that compound f26 is exploitable as a potential lead compound for the development of new alpha-glucosidase inhibitors with antidiabetic activity.