To discover novel multifunctional agents for the treatment of Alzheimer’s disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC₅₀ = 9.18 × 10⁻⁵ and 6.16 × 10⁻⁴ μM, respectively), good MAO-B inhibitory activity (IC₅₀ = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu²⁺-induced Aβ_1-42 aggregation inhibitory potency, disaggregation ability on Aβ_1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.

为了发现治疗阿尔茨海默病的新型多功能药物，设计、合成和评估了一系列 3-亚苄基/苄基苯酞曼尼希碱衍生物。生物筛选结果表明，这些衍生物大多表现出良好的多功能活性。其中，化合物( Z )-13c因其优异的多功能生物活性而引起了人们的特别关注。它显示出优异的Ee AChE 和Hu AChE 抑制（IC ₅₀  = 9.18 × 10 ^-5和 6.16 × 10 ^-4 μM，分别），良好的 MAO-B 抑制活性（IC ₅₀ = 5.88 μM）和高抗氧化活性（ORAC = 2.05 Trolox 当量）。此外，它还表现出良好的抗血小板聚集活性、中等的自身和Cu ²⁺诱导的A β _1-42聚集抑制效力、对A β _1-42原纤维的解聚能力、生物金属螯合能力、适当的BBB渗透性和显着的神经保护作用。此外，( Z )-13c还可以改善东莨菪碱诱导的小鼠学习记忆障碍。这些多功能特性突出了化合物( Z )-13c作为进一步开发抗 AD 多功能药物的有希望的候选者。