Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c₂ displayed the mighty inhibitory activity to hAChE (IC₅₀ = 0.053 μM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c₂ bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c₂ as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c₂ rescued BV-2 cells from H₂O₂-induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c₂, we observed that 4c₂ could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c₂ was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c₂ was a promising multi-targeted agent for treating AD.

阿尔茨海默病 (AD) 具有复杂的发病机制。目前，多靶点药物被认为具有通过同时触发功能互补途径中的分子来对抗 AD 的潜力。因此，设计合成了一系列基于富马酸二甲酯、曲尼司特和二硫代碳酸酯药效学特征的分子。这些化合物在体外显示出显着的 AChE 抑制活性。其中，化合物4c ₂对hAChE具有很强的抑制活性（IC ₅₀  = 0.053 μM）并具有穿过BBB的能力。动力学研究和分子对接指出4c ₂与hAChE的活性位点很好地结合，与hAChE中的关键残基形成稳定而牢固的相互作用。此外，4c ₂作为 Nrf2 激活剂可以促进 Nrf2 蛋白的核转位，并诱导 Nrf2 依赖性酶 HO-1、NQO1 和 GPX4 的表达。此外，4c _{2从 H 2} O ₂诱导的损伤中拯救了 BV-2 细胞并抑制了 ROS 的积累。对于4c ₂的抗神经炎症潜力，我们观察到4c ₂可以降低促炎细胞因子（NO、IL-6 和 TNF-α）的水平并抑制 iNOS 和 COX-2 的表达。特别是4c ₂在小鼠中耐受良好（2500 mg/kg，po），并在东莨菪碱诱导的小鼠模型中有效恢复了记忆障碍。总体而言，这些结果强调了4c ₂是一种很有前途的治疗 AD 的多靶点药物。