In addition to amyloid cascade hypothesis, ferroptosis – a recently identified cell death pathway associated with the accumulation of lipid hydroperoxides – was hypothesized as one of the main forms of cell death in Alzheimer's disease. Herein, a series of hydroxylated chalcones were designed and synthesized as dual-functional inhibitors to inhibit amyloid-β peptide (Aβ) aggregation as well as ferroptosis simultaneously. Thioflavin-T assay indicated trihydroxy chalcones inhibited Aβ aggregation better. In human neuroblastoma SH-SY5Y cells, cytoprotective chalcones 14a-c with three hydroxyl substituents exhibited a significant neuroprotection against Aβ_1-42 aggregation induced toxicity. In addition, chalcones 14a-c were found to be good inhibitors of ferroptosis induced by either pharmacological inhibition of the hydroperoxide-detoxifying enzyme Gpx4 using (1S, 3R)-RSL4 or cystine/glutamate antiporter system X_c⁻ inhibition by erastin through lipid peroxidation inhibition mechanism. Trihydroxy chalcone 14a was also able to completely subvert lipid peroxidation induced by Aβ_1-42 aggregation in SH-SY5Y cells indicating that they can reduce the neurotoxicity involved with oxidative stress. Compound 14a-c showed good ADMET properties and blood-brain barrier penetration in silico simulation software. From these data, a picture emerges wherein trihydroxy chalcones are potential candidates for the treatment of Alzheimer's disease by simultaneously inhibition of Aβ_1-42 aggregation and ferroptosis.

除淀粉样蛋白级联假说外，铁蛋白增生症（一种最近发现的与脂质过氧化氢的积累有关的细胞死亡途径）被认为是阿尔茨海默氏病的主要细胞死亡形式之一。本文中，设计并合成了一系列羟基化的查耳酮作为双功能抑制剂，以同时抑制淀粉样β肽（Aβ）的聚集以及肥大症。硫黄素-T测定表明三羟基查耳酮更好地抑制了Aβ聚集。在人神经母细胞瘤SH-SY5Y细胞中，具有三个羟基取代基的细胞保护查耳酮14a-c对_Aβ1-42聚集诱导的毒性表现出显着的神经保护作用。此外，查尔孔涅斯14a-c被发现是通过使用过氧化氢-酶解毒的Gpx4任一药理学抑制（感应ferroptosis的良好抑制剂1S，3R）或-RSL4胱氨酸/谷氨酸反向转运蛋白系统X _Ç ^-抑制erastin通过脂质过氧化抑制机制。三羟基查尔酮14a还能够完全破坏SH-SY5Y细胞中_Aβ1-42聚集诱导的脂质过氧化反应，表明它们可以减少与氧化应激有关的神经毒性。化合物14a-c在计算机模拟软件中显示出良好的ADMET性能和血脑屏障渗透性。从这些数据中可以看出，其中三羟基查耳酮通过同时抑制_Aβ1-42聚集和肥大症而成为治疗阿尔茨海默氏病的潜在候选者。