College of Chemistry and Pharmaceutical Engineering , Nanyang Normal University , Nanyang , 473061 , China.
Institute of Traditional Chinese Medicine Pharmacology and Toxicology , Sichuan Academy of Chinese Medicine Sciences , Chengdu , 610041 , China.
ACS Chem Neurosci. 2019 Feb 20;10(2):1008-1024. doi: 10.1021/acschemneuro.8b00530. Epub 2019 Jan 4.
A novel series of ferulic acid derivatives was designed and synthesized on the basis of the multi-target-directed ligands strategy for the treatment of Alzheimer's disease (AD). In vitro results revealed that all the target compounds were highly effective and selective butyrylcholinesterase (BuChE) inhibitors. In particular, compound TM-10 showed the best BuChE inhibitory activity, with IC = 8.9 nM, and remarkable monoamine oxidase A and B inhibitory potency, with IC = 6.3 and 8.6 μM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced amyloid-β peptide (Aβ) aggregation. In addition, TM-10 exhibited potent antioxidant activity (ORAC = 0.52 equiv) and neuroprotective effect against Aβ-mediated SH-SY5Y neurotoxicity, and it acted as an autophagic activator. TM-10 also showed good blood-brain barrier penetration. Furthermore, TM-10 exhibited a favorable dyskinesia recovery rate and response efficiency on an AlCl-induced zebrafish AD model and a potent neuroprotective effect on Aβ-induced zebrafish vascular injury. Further, in vivo assays demonstrated that TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopolamine-induced memory deficit in mice. Therefore, the present study displays evidence that TM-10 is a potent, multi-functional agent against AD and could be a promising lead candidate for anti-Alzheimer's disease drug development.
基于多靶点导向配体策略，我们设计并合成了一系列新型阿魏酸衍生物，用于治疗阿尔茨海默病（AD）。体外研究结果表明，所有目标化合物均为高效且选择性的丁酰胆碱酯酶（BuChE）抑制剂。特别是化合物 TM-10 对 BuChE 的抑制活性最好，IC = 8.9 nM，对单胺氧化酶 A 和 B 的抑制作用也非常显著，IC = 6.3 和 8.6 μM。TM-10 可以抑制（53.9%）和分散（43.8%）自身诱导的淀粉样β肽（Aβ）聚集。此外，TM-10 具有很强的抗氧化活性（ORAC = 0.52 equiv）和对 Aβ介导的 SH-SY5Y 神经毒性的神经保护作用，并且可以作为自噬激活剂。TM-10 还具有良好的血脑屏障穿透性。此外，TM-10 对 AlCl 诱导的斑马鱼 AD 模型表现出良好的运动障碍恢复率和反应效率，以及对 Aβ诱导的斑马鱼血管损伤的有效神经保护作用。进一步的体内试验表明，TM-10 具有较低的急性毒性，并且跳台被动回避试验表明，该化合物可以改善东莨菪碱诱导的小鼠记忆缺失。因此，本研究表明 TM-10 是一种针对 AD 的有效、多功能药物，可能成为开发抗阿尔茨海默病药物的有前途的候选药物。
