Oxazole-4-carboxamide/butylated hydroxytoluene hybrids with GSK-3β inhibitory and neuroprotective activities against Alzheimer's disease

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.