Ameliorative Effects of a Naphthoquinone Derivative With β‐Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice

Accumulation of amyloid‐β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)‐induced mice. Compound 888 (2‐(4‐(2,3,4‐trimethoxybenzyl)piperazin‐1‐yl)naphthalene‐1,4‐dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC 50 = 0.14 μM), and was more potent than the reference compound curcumin (IC 50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)‐A, MAO‐B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget‐directed ligands. TPN was permeable through the blood‐brain barrier, and non‐toxic to MDCK and SH‐SY5Y cells. TPN displayed prolonged and stable interactions with Aβ 42 during molecular dynamics simulations, in contrast to the short‐lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN‐treatment in behavioral tests. TPN treatment attenuated Aβ‐related protein expression, inflammatory responses, oxidative stress‐related changes, and apoptosis‐related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid‐related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive‐protective and neuroprotective potential under scopolamine‐induced impairment conditions and warrants further validation in AD‐relevant models.