Alzheimer’s disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood–brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aβ_1–42 aggregation. Observing the neuroprotection ability of 12o against H₂O₂-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.

中文翻译：

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基于阿魏酸模板的靶向 NLRP3 炎症小体的新型多功能配体用于治疗阿尔茨海默病的设计、合成和生物学评价

阿尔茨海默病 (AD) 是痴呆症的最常见原因，其起因是乙酰胆碱和丁酰胆碱水平低、氧化应激增加、炎症、金属稳态失衡、Aβ 和 tau 蛋白聚集。目前用于治疗 AD 的药物只能缓解症状，而不会干扰该疾病的病理特征。在我们不断努力开发自然灵感的新型 AD 多功能分子的过程中，对EJMC-4e进行了系统的 SAR 研究，以改善其多功能特性。经过严格的医学努力， 12o得到了开发，与EJMC-4e相比，其抗氧化特性提高了 15 倍，针对 AChE 和 BChE 的活性提高了 2 倍。分子对接和动力学研究揭示了12o与AChE和BChE复合物的结合位点和稳定性。 PAMPA-BBB 测定清楚地表明12o可以轻松穿过血脑屏障。有趣的是，12o还表现出有希望的金属螯合活性，而EJMC-4e被发现缺乏这种特性。此外，12o抑制金属诱导的或自身的 Aβ _1-42聚集。观察12o对PC-12 细胞系中H ₂ O ₂诱导的氧化应激的神经保护能力是值得注意的。此外，12o还抑制 NLRP3 炎性体激活，并减轻 HMC-3 细胞中由 LPS 和 ATP 引起的线粒体诱导的 ROS 和 MMP 损伤。此外，12o能够有效降低AD果蝇模型中的线粒体和细胞氧化应激。最后，12o可以逆转东莨菪碱诱导的 AD 小鼠模型的记忆损伤，这一点通过体内和离体研究得到了证实。这些发现表明，该化合物可能作为进一步改善 AD 治疗的有希望的候选药物。