Complex pathomechanism of Alzheimer's disease (AD) prompts researchers to develop multifunctional molecules in order to find effective therapy against AD. We designed and synthesized novel multifunctional ligands for which we assessed their activities towards butyrylcholinesterase, beta secretase, amyloid beta (Aβ) and tau protein aggregation as well as antioxidant and metal-chelating properties. All compounds showed dual anti-aggregating properties towards Aβ and tau protein in the in cellulo assay in Escherichia coli. Of particular interest are compounds 24b and 25b, which efficiently inhibit aggregation of Aβ and tau protein at 10 μM (24b: 45% for Aβ, 53% for tau; 25b: 49% for Aβ, 54% for tau). They display free radical scavenging capacity and antioxidant activity in ABTS and FRAP assays, respectively, and selectively chelate copper ions. Compounds 24b and 25b are also the most potent inhibitors of BuChE with IC50 of 2.39 μM and 1.94 μM, respectively. Promising in vitro activities of the presented multifunctional ligands as well as their original scaffold are a very interesting starting point for further research towards effective anti-AD treatment.

中文翻译：

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基于1-苄基吡咯烷-3-胺的BuChE抑制剂具有抗聚集，抗氧化剂和金属螯合特性，可作为对抗阿尔茨海默氏病的多功能药物。

阿尔茨海默氏病（AD）的复杂发病机制促使研究人员开发多功能分子，以找到针对AD的有效疗法。我们设计并合成了新型多功能配体，针对这些配体我们评估了它们对丁酰胆碱酯酶，β分泌酶，淀粉样β（Aβ）和tau蛋白聚集的活性以及抗氧化剂和金属螯合特性。在大肠杆菌的细胞内测定中，所有化合物均显示出针对Aβ和tau蛋白的双重抗聚集特性。特别令人感兴趣的是化合物24b和25b，它们可有效抑制10μM的Aβ和tau蛋白的聚集（24b：Aβ为45％，tau为53％； 25b：Aβ为49％，tau为54％）。它们分别在ABTS和FRAP分析中显示出自由基清除能力和抗氧化活性，并选择性地螯合铜离子。化合物24b和25b也是BuChE的最强抑制剂，IC50分别为2.39μM和1.94μM。提出的多功能配体及其原始支架的有希望的体外活性是进一步研究有效抗AD治疗的一个非常有趣的起点。