The multi-target-directed ligands have been regarded as the promising multifunctional agents for the treatment of Alzheimer’s disease (AD). Based on our previous work, a series of genistein-O-alkylamines derivatives was developed to further explore the structure-activity-relationship. The results showed that compound 7d indicated reversible and highly selective hAChE inhibitory activity with IC value of 0.53 μM. Compound 7d also displayed good antioxidant activity (ORAC = 1.1 eq.), promising neuroprotective effect and selective metal chelation property. Moreover, compound 7d significantly inhibited self-induced, hAChE-induced and Cu-induced Aβ aggregation with 39.8%, 42.1% and 74.1%, respectively, and disaggregated Cu-induced Aβ aggregation (67.3%). In addition, compound 7d was a potential autophagy inducer and improved the levels of GPX4 protein. Furthermore, compound 7d presented good blood-brain-barrier permeability in vitro. More importantly, compound 7d did not show any acute toxicity at doses of up to 1000 mg/kg and presented good precognitive effect on scopolamine-induced memory impairment. Therefore, compound 7d was a promising multifunctional agent for the development of anti-AD drugs.
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