Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N -Aryl Galantamine Analogues.

A series of new N -aryl galantamine analogues ( 5a - 5x ) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N -aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative ( 5q ) (IC 50 = 0.19 μM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H 2 O 2 -induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q . Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.