A unique compound 3c targets GSK-3β and metal ion, interferes with tau and metal dyshomeostasis, promotes neurite outgrowth, decreases Aβ accumulation and ABTS•+, and enhances zebrafish motility.

As a progressive neurodegenerative condition, Alzheimer's disease (AD) can be caused by multiple pathological factors. In this study, we designed and synthesized three novel compounds targeting glycogen synthase kinase-3β (GSK-3β) and metal ion to interfere with the key pathological pathways involved in tau phosphorylation, metal dyshomeostasis, and amyloid-β (Aβ) accumulation. Notably, compound 3c demonstrated the greatest GSK-3β inhibitory effect (IC50 = 0.66 ± 0.19 nM) and favorable targeting specificity for GSK-3. 3c effectively inhibited GSK-3β activity possibly through enhancing the expression of p-GSK-3β-Ser9, thereby indirectly suppressing Aβ25-35-mediated tau-Ser396 phosphorylation. Additionally, 3c exhibited chelating effects toward pathogenic metal ions, effectively inhibited the accumulation of Cu2+-Aβ1-42 aggregates, and surprisingly, it directly targeted Aβ1-42. Moreover, 3c displayed additional anti-AD effects, including the upregulation of β-catenin and neurogenesis-associated biomarkers, the promotion of neurite outgrowth, and the scavenging of ABTS free radicals (ABTS•+). Notably, 3c obviously enhanced the motility of AD zebrafish and preliminarily demonstrated low toxicity. Together, we identified a distinct compound, 3c, with multiple anti-AD effects and potential as a drug candidate for further investigation.