Design and synthesis of new phosphazine and triazole derivatives for treatment of Alzheimer's disease: modulating ROS/JNK and Wnt/β-catenin signaling pathways

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and the accumulation of Amyloid-β (Aβ) peptides. In this study, a novel series of triazole and phosphazine derivatives were synthesized and evaluated for neuroprotective activity in an aluminum chloride (AlCl₃)-induced rat model of AD. Among the synthesized compounds, 3a, 6a, and 6c were structurally characterized and selected for in vivo biological evaluation. Behavioral, biochemical, molecular, and histopathological assessments were conducted to determine their efficacy, with Rivastigmine used as a reference drug. Compounds 3a and 6c significantly improved cognitive and memory performance, decreased Aβ_1-42 production, and reduced Reactive Oxygen Species (ROS) generation. Furthermore, both compounds inhibited the activation of JNK and Puma, promoted Beclin-1 expression, and activated Wnt/β-catenin signaling, as evidenced by increased expression levels of Wnt7a, β-catenin, LRP6, and FZD4, alongside decreased expression levels of GSK-3β and BACE1. Molecular docking studies supported these findings, revealing strong binding affinities of the active compounds, particularly 3a, to the JNK3 active site. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 3a to confirm the formation of a stable complex with JNK3. Compounds 3a, 6a, and 6c demonstrated favorable pharmacokinetic profiles, with predicted good oral bioavailability, blood-brain barrier permeability, and non-substrate behavior toward P-glycoprotein. They are expected to maintain therapeutic availability in systemic circulation, as indicated by the predicted plasma protein binding below 90%, moderate to high steady-state volume of distribution, and lack of substrate affinity for Cytochrome P450 enzymes CYP2C9 and CYP2D6. These results suggest that compounds 3a and 6c may serve as promising multi-target therapeutic candidates for AD by modulating oxidative stress, Apoptosis, Autophagy, and Wnt/β-catenin signaling pathways.