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

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.

Anti-diabetic activity; Thiosemicarbazide; α-Glucosidase; β-Carboline.