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

• Published in: European journal of medicinal chemistry 2023-12, Vol.261, p.115795-115795, Article 115795
• Main Authors: Xiao, Di, Lu, Li, Liang, Bingwen, Xiong, Zhuang, Xu, Xuetao, Chen, Wen-Hua
• Format: Article
• Language: English
• Subjects: 1,3,4-Oxadiazole; Antidiabetic activity; Mechanism of inhibitory action; α-Glucosidase; β-Carboline
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115795

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 IC50 values in the range of 3.07–15.49 μM, representing that they are 36∼183-fold more active than a positive control, acarbose (IC50 = 564.28 μM). Among them, compound f26 exhibited the highest α-glucosidase inhibitory activity (IC50 = 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. [Display omitted] •1,3,4-oxadiazolyl-containing β-carboline derivatives f1∼f35 were and synthesized.•All compounds showed potential α-glucosidase inhibitors.•The inhibition mechanism of f26 was investigated by multispectral methods.•f26 presented in vivo hypoglycemic activity in STZ-induced diabetic mice.