Design, synthesis, and bio-evaluation of C1-aryl galantamine derivatives

For exploring the naturally-inspired anti-AD multifunctional molecules, a series of C1-aryl galantamine derivatives 4a-x were designed and synthesized. The cholinesterase inhibition activity and neuroprotection ability of 4a-x were evaluated. Among them, meta-tbutylbenzene derivative 4b (IC₅₀ = 0.12 ± 0.03 μM) and para-hydroxybenzene derivative 4h (IC₅₀ = 3.86 ± 0.82 μM) exhibited selective inhibition effect against EeAChE and EqBChE, respectively. Compound 4k containing meta-methylthio benzene group exhibited dual inhibitory activity against EeAChE (IC₅₀ = 0.47 ± 0.13 μM) and EqBChE (IC₅₀ = 2.98 ± 0.80 μM). Furthermore, the neuroprotection experiment revealed that eight synthesized derivatives had significant effect to protect SH-SY5Y cells from H₂O₂-induced damage at a concentration of 25 μM. Notably, the dual AChE and BChE inhibitor 4k also exhibited the good neuroprotective activity, which deserves to be further explored for developing potential multifunctional AD drug.