1,2,3-Triazole-based betulinic acid derivatives as α-glucosidase inhibitors: Synthesis and in vitro and in vivo biological evaluation

• Published in: Journal of molecular structure 2024-08, Vol.1310, p.138294, Article 138294
• Main Authors: Zhang, Yufei, Li, Jiangyi, Min, Xiaofeng, Liang, Bingwen, Sun, Jinping, Lin, Keyin, Xiong, Zhuang, Xu, Xuetao, Chen, Wen-Hua
• Format: Article
• Language: English
• Subjects: Anti-diabetic activity; Betulinic acid; α-Glucosidase
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.138294

•1,2,3-Triazole-based betulinic acid derivatives were synthesized as α-glucosidase inhibitors.•All the derivatives exhibited excellent inhibition against α-glucosidase.•The most active compound d23 acted as a mixed-type inhibitor for α-glucosidase.•Compound d23 exerted its inhibitory activity by changing the conformation of α-glucosidase.•Compound d23 reduced fasting blood glucose level and improved glucose tolerance and dyslipidemia. A series of 1, 2, 3-triazole-based betulinic acid derivatives d1–d31 were synthesized as α-glucosidase inhibitors with hypoglycemic activity. All the derivatives exhibited excellent inhibition against α-glucosidase, and compound d23 was the most active (IC50 = 2.83 ± 0.19 μM). Inhibition kinetics showed that compound d23 was a mixed-type inhibitor for α-glucosidase. Spectroscopic studies based on 3D fluorescence and circular dichroism spectra suggested that compound d23 exerted its inhibitory activity by changing the conformation of α-glucosidase. Molecular docking revealed that compound d23 was well nested into the active pocket of α-glucosidase through hydrogen-bonding and hydrophobic interactions. In vivo experiments showed that compound d23 could not only reduce the level of fasting blood glucose, but also improve glucose tolerance and dyslipidemia. The present findings strongly suggest that compound d23 is exploitable as a leading compound for the development of α-glucosidase inhibitors in the treatment of type 2 diabetes. [Display omitted]