A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer’s disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC₅₀, 12.91∼62.52 μM for AChE and 0.094∼13.72 μM for BuChE). Specifically, compound 1 showed the highest inhibitory activity against BuChE with the IC₅₀ value of (0.094±0.0054) μM. A Lineweaver-Burk plot and molecular docking studies demonstrated that 1 targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of BuChE. Besides, all derivatives showed excellent hydroxyl free radicals (·OH) scavenging ability than vitamin C and cyclic voltammetry results displayed that 1 could effectively scavenge superoxide anion radical (·O₂^-). In addition, compound 1 displayed good metal chelating properties and had anti-Aβ aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments.

一系列柚皮素衍生物被设计和合成为多功能抗阿尔茨海默病 (AD) 药物。结果表明，这些衍生物在微摩尔范围内显示出中等至良好的乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制活性（IC ₅₀，AChE 为 12.91∼62.52 μM，BuChE 为 0.094∼13.72 μM）。具体而言，化合物 1 对 BuChE 的抑制活性最高，IC ₅₀(0.094±0.0054) μM 的值。Lineweaver-Burk 图和分子对接研究表明，1 同时靶向 BuChE 的催化活性位点 (CAS) 和外围阴离子位点 (PAS)。此外，所有衍生物均表现出比维生素C优异的羟基自由基(·OH)清除能力，循环伏安法结果表明1能有效清除超氧阴离子自由基(·O ₂ ^- )。此外，化合物1显示出良好的金属螯合特性并具有抗Aβ聚集活性。因此，化合物 1 可能是进一步开发的潜在抗 AD 药物。