Shi_2025_Eur.J.Med.Chem_303_118437

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 beta-amyloid (Abeta(1-42)) aggregation inhibition. Among them, compound 7a emerged as a synergistic multifunctional agent with significant inhibition of AChE (EeAChE: IC(50) = 0.21 microM; HsAChE: IC(50) = 13 nM) and anti-Abeta activity (IC(50) = 2.92 microM for self-induced Abeta(1-42) aggregation; IC(50) = 1.28 microM for disaggregation of Abeta(1-42) fibrils; IC(50) = 3.72 microM for Cu(2+)-induced Abeta(1-42) aggregation; IC(50) = 2.16 microM for disaggregation of Cu(2+)-induced Abeta(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.