Wang_2025_Fitoterapia_183_106535

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 (IC(50) = 0.12 +/- 0.03 microM) and para-hydroxybenzene derivative 4h (IC(50) = 3.86 +/- 0.82 microM) exhibited selective inhibition effect against EeAChE and EqBChE, respectively. Compound 4k containing meta-methylthio benzene group exhibited dual inhibitory activity against EeAChE (IC(50) = 0.47 +/- 0.13 microM) and EqBChE (IC(50) = 2.98 +/- 0.80 microM). Furthermore, the neuroprotection experiment revealed that eight synthesized derivatives had significant effect to protect SH-SY5Y cells from H(2)O(2)-induced damage at a concentration of 25 microM. 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.