Neuronal cells overexpressing phosphorylated Tau proteins can increase the susceptibility to oxidative stress. Regulation of glycogen synthase-3β (GSK-3β) and reduction of Tau protein hyperphosphorylation, along with alleviation of oxidative stress, may be an effective way to prevent or treat Alzheimer's disease (AD). For this purpose, a series of Oxazole-4-carboxamide/butylated hydroxytoluene hybrids were designed and synthesized to achieve multifunctional effects on AD. The biological evaluation showed that the optimized compound KWLZ-9e displayed potential GSK-3β (IC₅₀ = 0.25 μM) inhibitory activity and neuroprotective capacity. Tau protein inhibition assays showed that KWLZ-9e reduced the expression of GSK-3β and downstream p-Tau in HEK GSK-3β 293T cells. Meanwhile, KWLZ-9e could alleviate H₂O₂-induced ROS damage, mitochondrial membrane potential imbalance, Ca²⁺ influx and apoptosis. Mechanistic studies suggest that KWLZ-9e activates the Keap1-Nrf2-ARE signaling pathway and enhances the expression of downstream oxidative stress proteins including TrxR1, HO-1, NQO1, GCLM to exert cytoprotective effects. We also confirmed that KWLZ-9e could ameliorate learning and memory impairments in vivo model of AD. The multifunctional properties of KWLZ-9e suggest that it is a promising lead for the treatment of AD.

过度表达磷酸化 Tau 蛋白的神经元细胞可以增加对氧化应激的易感性。糖原合酶 3β (GSK-3β) 的调节和 Tau 蛋白过度磷酸化的减少，以及氧化应激的减轻，可能是预防或治疗阿尔茨海默病 (AD) 的有效方法。为此，设计并合成了一系列恶唑-4-甲酰胺/丁基化羟基甲苯杂化物，以实现对 AD 的多功能作用。生物学评价表明，优化后的化合物KWLZ-9e显示出潜在的 GSK-3β (IC ₅₀  = 0.25 μM) 抑制活性和神经保护能力。Tau 蛋白抑制测定表明KWLZ-9e降低 HEK GSK-3β 293T 细胞中 GSK-3β 和下游 p-Tau 的表达。同时，KWLZ-9e可减轻H ₂ O ₂诱导的ROS损伤、线粒体膜电位失衡、Ca ²⁺内流和细胞凋亡。机制研究表明，KWLZ-9e激活 Keap1-Nrf2-ARE 信号通路并增强下游氧化应激蛋白（包括 TrxR1、HO-1、NQO1、GCLM）的表达以发挥细胞保护作用。我们还证实KWLZ-9e可以改善 AD 体内模型的学习和记忆障碍。KWLZ-9e的多功能特性表明它是治疗 AD 的有前景的先导化合物。