Abd_2026_Bioorg.Chem_183_110578

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction and oxidative stress, making the development of multi-target-directed ligands (MTDLs) an attractive therapeutic strategy. Herein, we designed and synthesized a novel series of pyrimidinone-based acyl hydrazones 6a-g bearing substituted aryl or heteroaryl (furan) moieties. The synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibitory and antioxidant activities. The synthesized pyrimidinone-based acyl hydrazones (6a-g) exhibited promising acetylcholinesterase (AChE) inhibitory activity. Compound 6 g emerged as the most potent inhibitor, with an IC50 value of 4.79 microM, corresponding to approximately 55.7-fold greater potency than tacrine hydrochloride (IC50 = 266 microM) under standardized parallel assay conditions. Compounds 6a, 6b, and 6f also demonstrated potent AChE inhibition, with IC50 values ranging from 15.9 to 128.65 microM, whereas the remaining derivatives exhibited moderate to weak inhibitory activity. The synthesized compounds also displayed promising antioxidant activity in DPPH and nitric oxide (NO) radical scavenging assays. Notably, 6g exhibit potent DPPH and nitric oxide radical scavenging activity, surpassing standard antioxidant (ascorbic acid) by approximately 35-fold and 9-fold, respectively. Molecular docking studies supported the experimental results by revealing favorable binding modes of the most active compounds within the AChE active site, while suggesting potential computationally predicted interactions with BuChE, 5-LOX, and COX-2. Furthermore, in silico drug-likeness and ADME analyses provided baseline pharmacokinetic profiles, guiding rational structural optimization strategies to enhance blood-brain barrier permeability. These findings identify pyrimidinone-based acyl hydrazones as promising multifunctional lead compounds for the development of novel therapeutic agents against Alzheimer's neurocognitive disorder.