Novel thiosemicarbazide-based β-carboline derivatives as α-glucosidase inhibitors: Synthesis and biological evaluation

• Published in: European journal of medicinal chemistry 2024-09, Vol.275, p.116595, Article 116595
• Main Authors: Liang, Bingwen, Xiao, Di, Wang, Shao-Hua, Xu, Xuetao
• Format: Article
• Language: English
• Subjects: Anti-diabetic activity; Thiosemicarbazide; α-Glucosidase; β-Carboline
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116595

In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based β-carboline derivatives (CTL1∼36) were synthesized and evaluated. CTL1∼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC50 values ranging from 2.81 to 12.40 μM, significantly surpassing the positive control acarbose (IC50 = 564.28 μM). Notably, CTL26 demonstrated the most potent inhibition (IC50 = 2.81 μM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential. [Display omitted] •Thirty-six novel thiosemicarbazide-based β-carboline derivatives were synthesized.•All compounds showed potential α-glucosidase inhibitory activity.•The inhibition mechanism of CTL26 was investigated by multispectral methods.•CTL26 presented in vivo hypoglycemic activity in STZ-induced diabetic mice.