Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
Institute for Innovative Drug Design and Evaluation, Henan University, Kaifeng 475004, People's Republic of China.
Bioorg Med Chem. 2020 Jan 1;28(1):115190. doi: 10.1016/j.bmc.2019.115190. Epub 2019 Nov 9.
A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver-Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn't show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer's disease.
一系列新型的 gravolinine 衍生物被合成并评估为潜在的抗阿尔茨海默病药物。化合物 5f 对乙酰胆碱酯酶 (AChE) 表现出最好的抑制活性，并且对丁酰胆碱酯酶 (BuChE) 具有惊人的抑制活性，IC 值分别为 0.72 μM 和 0.16 μM。Lineweaver-Burk 图和分子建模研究的结果表明，化合物 5f 对 AChE 的抑制是非竞争性的。此外，这些衍生物表现出很强的自诱导β-淀粉样蛋白 (Aβ) 聚集抑制作用。此外，5f 在 50 μM 时对 PC12 和 HepG2 细胞没有明显的毒性。最后，体内研究证实 5f 能显著改善东莨菪碱处理的 ICR 小鼠的认知能力。因此，这些 gravolinine 衍生物应该被深入和系统地研究用于治疗阿尔茨海默病。
