Benzylpiperidine-pyridazin-3(2H)-one derivatives as potential multifunctional agents against Alzheimer's disease

Based on multitarget-directed-ligands (MTDLs) strategy, a series of benzylpiperidine-pyridazin-3(2H)-ones were designed, synthesized and evaluated as innovative multifunctional agents for Alzheimer's disease (AD). Biological evaluation revealed that most compounds exhibited excellent acetylcholinesterase (AChE) inhibition, potent antioxidant activity and moderate β-amyloid (Aβ_1-42) aggregation inhibition. Among them, compound 7a emerged as a synergistic multifunctional agent with significant inhibition of AChE (EeAChE: IC₅₀ = 0.21 μM; HsAChE: IC₅₀ = 13 nM) and anti-Aβ activity (IC₅₀ = 2.92 μM for self-induced Aβ_1-42 aggregation; IC₅₀ = 1.28 μM for disaggregation of Aβ_1-42 fibrils; IC₅₀ = 3.72 μM for Cu²⁺-induced Aβ_1-42 aggregation; IC₅₀ = 2.16 μM for disaggregation of Cu²⁺-induced Aβ_1-42 fibrils). In addition, 7a was endowed with the potential to serve as antioxidant (2.88 Trolox equivalents), metals chelator and anti-neuroinflammatory agent for synergistic treatment. Moreover, 7a exhibited pronounced neuroprotective effects across multiple cellular models. Pharmacokinetically, 7a displayed favorable brain penetration (AUC_brain/plasma = 0.77) and sustained exposure. In vivo evaluation demonstrated that 7a effectively ameliorated scopolamine-induced cognitive impairment in the Morris water maze, which was associated with restored cholinergic function and mitigated oxidative stress in mice. The synergistic multi-target efficacy combined with favorable pharmacokinetic properties underscores its potential as a disease-modifying therapeutic agent for AD.