Design, synthesis and evaluation of salicylic acid-donepezil hybrids as functional agents for the treatment of Alzheimer’s disease

In this work, a series of salicylic acid derivatives was designed through the multi-target-directed ligand strategy (MTDLs). The synthesized compounds were evaluated as multifunctional agents. The in vitro biological activity results revealed that compound 3a was a selective eqBuChE inhibitor (IC50 = 0.29 μM), compound 3k was a selective eeAChE inhibitor (IC50 = 0.77 μM), and compound 3p was a selective eqBuChE inhibitor (IC50 = 0.82 μM). Compounds 3a, 3k and 3p also showed good antioxidant activity and anti-inflammatory property. Furthermore, compounds 3a, 3k and 3p were selective metal chelators. Moreover, compounds 3a, 3k and 3p showed significant neuroprotective effects on H2O2-/Aβ25-35-induced PC12 cells injury. More importantly, compounds 3a, 3k and 3p possessed favorable ADME properties. Taken together, compounds 3a, 3k and 3p were promising multifunctional agents, deserving further investigations.