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

In this study, we designed and synthesized a novel class of 1,3,4-oxadiazolyl-containing β-carboline derivatives, i.e., compounds f1∼f35 as potential α-glucosidase inhibitors. All the synthesized compounds possessed outstanding α-glucosidase inhibitory activity with the IC ₅₀ values in the range of 3.07-15.49 μM, representing that they are 36∼183-fold more active than a positive control, acarbose (IC ₅₀  = 564.28 μM). Among them, compound f26 exhibited the highest α-glucosidase inhibitory activity (IC ₅₀  = 3.07 μM) 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 α-glucosidase through hydrogen bonds and hydrophobic interactions, led to changes in the conformation and secondary strictures of α-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 α-glucosidase inhibitors with antidiabetic activity.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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