A series of novel ferulic acid-O-alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced β-amyloid (Aβ) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor (IC50 value of 0.021 μM for equine serum BuChE, 8.63 μM for ratBuChE and 0.07 μM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50 = 2.13 μM for electric eel AChE, 1.8 μM for ratAChE and 3.82 μM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced Aβ1-42 aggregation (50.8 ± 0.82%) and was found to disaggregate self-induced Aβ1-42 aggregation (38.7 ± 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H2O2-induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro. Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD.
Keywords: Alzheimer's disease; Antioxidant activity; Aβ aggregation; Butyrylcholinesterase inhibition; Ferulic acid-O-alkylamines derivatives; Multifunctional agents; Neuroprotective effects.
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