Tran_2026_Bioorg.Med.Chem_142_118778

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder requiring multi-target-directed ligands (MTDLs) to simultaneously modulate cholinergic dysfunction and amyloid-beta pathology. In this study, a series of hydrazone-linked pyridin-1-ium salts was rationally designed and synthesized by integrating key pharmacophores of acetylcholinesterase (AChE) and beta-secretase 1 (BACE-1) inhibitors into a compact scaffold. Biological evaluation revealed potent AChE inhibitory activity for most compounds, with several derivatives outperforming donepezil. Compound 8b exhibited the highest potency (IC(50) = 0.026 +/- 0.005 microM). Structure-activity relationship analysis indicated that small, moderately polar substituents enhanced AChE inhibition, whereas the introduction of bulkier groups into this series led to a relative improvement in BACE-1 inhibitory activity. Kinetic studies on AChE suggested a mixed-type inhibition mechanism. Molecular docking favored key Pi-Pi and Pi-cation interactions within the AChE gorge, while hydrophobic interactions contributed to BACE-1 binding. Complementing the static docking analysis, all-atom MD simulations further supported persistent residence of compound 8b within both AChE and BACE-1 binding sites, with interaction fingerprints refining the docking model by revealing dominant hydrophobic/Pi-Pi contacts in AChE and dynamic Pi-cation/hydrophobic contacts in BACE-1. In silico ADMET analysis demonstrated favorable drug-like properties. These findings highlight hydrazone-linked pyridin-1-ium salts as promising scaffolds for developing compact multi-targeted agents for AD.