Hydroxyl chalcone derivative DK02 as a multi‐target‐directed ligand for Alzheimer's disease: A preclinical study in zebrafish

Background and Purpose Alzheimer's disease (AD) is a widespread neurodegenerative condition characterized by amyloid‐beta (Aβ) plaques and tau protein aggregates, leading to significant cognitive decline. Existing treatments primarily offer symptomatic relief, underscoring the urgent need for novel therapies that address multiple AD pathways. This study evaluates the efficacy of DK02, a hydroxyl chalcone derivative, in a scopolamine‐induced dementia model in zebrafish, hypothesizing that it targets several neurodegenerative mechanisms simultaneously. Experimental Approach We employed a blend of experiments, including in silico docking, in vitro enzyme inhibition assays and in vivo zebrafish models, to assess therapeutic effects of DK02. Methods included molecular docking to forecast interaction sites, acetylcholinesterase (AChE) inhibition testing, and various behavioural and histopathological analyses to gauge DK02's cognitive and neuroprotective impacts. Key Results DK02 emerged as a potent AChE inhibitor via virtual screening, and significantly enhanced cognitive functions in zebrafish, by improving memory retention and reducing anxiety‐like behaviours. DK02 also displayed strong antioxidant properties, reducing oxidative stress‐induced neuronal damage. Histopathological analysis confirmed its neuroprotective effects by showing decreased amyloid plaque burden and mitigated structural brain damage. Conclusion and Implications DK02 shows promise as a multi‐target‐directed ligand for AD, offering a new therapeutic path by simultaneously addressing cholinergic, oxidative and amyloid pathways. Its potential to enhance cognitive functions and curtail neurodegeneration suggests advantages over current symptomatic treatments. Further research into DK02 mechanisms and long‐term impacts is essential for its development in AD therapy.