Novel C3‐Aminated Galantamine Derivatives as Selective Butyrylcholinesterase Inhibitors With Neuroprotective Effects

To explore natural‐inspired novel anti‐AD bioactive molecules, a series of galantamine derivatives 6a – 6u were synthesized via Pd‐catalyzed Buchwald–Hartwig cross‐coupling, with various nitrogen‐containing functional groups installed at the C3 position of galantamine. Compared with galantamine, these compounds showed greatly enhanced selective BChE inhibition activity, suggesting that the C3 position of galantamine might be a key modifiable site for developing new selective BChE inhibitors. Among them, the derivative 6l which contained a 3,5‐difluoroaniline structure moiety exhibited promising selective inhibitory activity against eq BChE, with an IC ₅₀ of 0.88 μM and a selectivity index of 26.2. Molecular docking and molecular dynamics simulations were performed to elucidate the interaction model between compound 6l and BChE. Moreover, 6l also showed favorable neuroprotection potency against H ₂ O ₂ injured SH‐SY5Y cells. Preliminary mechanistic study revealed that compound 6l could mitigate oxidative stress and suppress cellular apoptosis. This work not only offers a novel galantamine analog with promising in vitro cholinesterase inhibitory and neuroprotective effects for further anti‐AD study, but also provides new insights into the structure optimization of natural drug galantamine.