Development of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives as multifunctional agents for Alzheimer’s disease treatment

Due to the complex pathogenesis of AD, the multitarget-directed ligands (MTDLs) strategy presented the best pharmacological option for AD treatment. Herein, a series of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives (5a–f and 6a–f) was rationally designed and synthesized. Of these derivatives, 5c was a good multifunctional agent (eeAChE IC50 = 7.9 μM, MAO-B IC50 = 9.9 μM, BACE1 IC50 = 8.3 μM) in vitro and displayed a mixed-type AChE inhibition, which could bind to the CAS and PAS of AChE. Compound 5c also exhibited good antioxidant activity (ORAC = 2.5 eq) and neuroprotective effects. Furthermore, compound 5c was a selective metal ions chelator. And it could cross blood–brain barrier in vitro and complied with drug-like properties rule of 5. Therefore, compound 5c was a promising multifunctional agent for the treatment of AD.