Design, synthesis and biological evaluation of novel betulinic acid derivatives containing 1,2,4-triazole-derived schiff bases as α-glucosidase inhibitors

• Published in: Journal of molecular structure 2024-11, Vol.1315, p.138889, Article 138889
• Main Authors: Zhang, Yufei, Yu, Xiaoyan, Li, Jiangyi, Liang, Bingwen, Sun, Jinping, Min, Xiaofeng, Xiong, Zhuang, Chen, Wen-Hua, Xu, Xuetao
• Format: Article
• Language: English
• Subjects: 1, 2, 4-triazole; Anti-diabetic activity; Betulinic acid; Inhibition; α-Glucosidase
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.138889

•Novel betulinic acid derivatives containing 1,2,4-triazole- derived schiff base f1–f35 were synthesized and screened against α-glucosidase.•Compound f32 showed the highest α-glucosidase inhibitory with IC50 of 1.52±0.16 μM.•Inhibition kinetics showed that compound f32 was a non-competitive inhibitor for α-glucosidase.•Spectroscopic studies based on three dimensional fluorescence and circular dichroism and molecular docking suggested that compound f32 interacted with α-glucosidase.•In vivo experiments showed that compound f32 could not only reduce the level of fasting blood glucose, but also improve glucose tolerance and dyslipidemia. A series of novel betulinic acid (BA) derivatives containing 1,2,4-triazole- derived schiff base have been designed and synthesized as α-glucosidase inhibitors. All the title compounds showed higher α-glucosidase inhibitory activity than acarbose and BA, with compound f32 showing the highest α-glucosidase inhibitory activity (IC50 = 1.52±0.16 μM). Lineweaver-Burk plot analysis suggested that compound f32 was a non-competitive inhibitor for α-glucosidase. 3D fluorescence and circular dichroism spectroscopy disclosed the interaction of compound f32 with α-glucosidase by changing the secondary structure of α-glucosidase. Molecular docking showed that compound f32 could bind to the active site of α-glucosidase through hydrogen bonding and hydrophobic interaction. More importantly, compound f32 could not only reduce the level of fasting blood glucose and postprandial blood glucose in mice, but also ameliorate dyslipidemia. The current findings suggest that compound f32 may serve as a leading compound for the discovery of α-glucosidase inhibitors in the treatment of type 2 diabetes. [Display omitted]