Donepezil-derived multi-target-directed ligands: design, synthesis, and anti-Alzheimer's evaluation.

Alzheimer's disease (AD), a leading cause of dementia with high mortality and disability, has prompted the emergence of multi-target drug development as a key therapeutic strategy due to its complex and not yet fully understood pathogenesis. Herein, we present new multi-target-directed ligands combining pharmacophore fragments capable of simultaneously inhibiting key enzymes implicated in AD pathology. These compounds exhibit inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and β-secretase (BACE-1), while also demonstrating anti-aggregation effects on β-amyloid (Aβ) and hyperphosphorylated tau (p-tau), both of which contribute to neurodegeneration. Among the synthesized series, compound 13f illustrated a well-balanced inhibitory profile, with IC₅₀ values of 0.387 μM for AChE, 0.430 μM for BuChE, and 0.531 μM for BACE-1. Furthermore, In vivo studies revealed that compound 13f effectively reduced AChE concentrations in the brain by 30%, alongside a more substantial suppression of BuChE and BACE-1, with reductions of 60% and 62%, respectively. Additionally, 13f reduced Aβ and p-tau brain aggregates concentrations by over 30%, highlighting its potential as a promising lead for further optimization. These findings offer a compelling foundation for the development of effective multi-target directed ligands (MTDLs) for AD intervention.