Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease

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 beta-amyloid (A beta) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor ( IC50 value of 0.021 mu M for equine serum BuChE, 8.63 mu M for ratBuChE and 0.07 mu M for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50 = 2.13 mu M for electric eel AChE, 1.8 mu M for ratAChE and 3.82 mu M 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 selfinduced A beta(1-42) aggregation (50.8 +/- 0.82%) and was found to disaggregate self- (i)nduced A beta(1-42) 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. (c) 2017 Elsevier Masson SAS. All rights reserved.