Abstract：
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.
摘要：
为了寻找有效的α-葡萄糖苷酶抑制剂来对抗糖尿病，合成并评估了一系列新型的基于氨基硫脲的β-咔啉衍生物（CTL1〜36）。CTL1~36对α-葡萄糖苷酶有明显的抑制作用，IC50值范围为2.81至12.40μM，显著超过阳性对照阿卡波糖(IC50=564.28μM)。值得注意的是,CTL26表现出最有效的抑制作用(IC50=2.81μM),并被表征为非竞争性抑制剂。通过荧光猝灭的组合测定，三维荧光光谱,CD光谱,和分子对接，我们阐明了CTL26通过氢键和疏水相互作用与α-葡萄糖苷酶形成复合物，导致α-葡萄糖苷酶构象改变，从而损害酶活性。体内研究表明，口服CTL26（25和50mg/kg/d）可降低空腹血糖水平，增强葡萄糖耐量，并改善糖尿病小鼠的脂质异常。这些发现将CTL26定位为开发具有抗糖尿病潜力的α-葡糖苷酶抑制剂的有希望的候选物。
