A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC50 = 2.6 μM) and selective MAO-B inhibitor (IC50 = 5.3 μM), which were supported by docking study. Compound TM-2 also showed good antioxidant activity, and was a selective metal chelator, as well as a neuroprotectant. Moreover, compound TM-2 could significantly inhibit self-induced and Cu2+-induced Aβ1-42 aggregation with 70.2% and 80.7% inhibition rate, respectively, and could disaggregate Cu2+-induced Aβ1-42 aggregation (73.5%), the further TEM images observed provided rational explanation. Besides, compound TM-2 displayed good PAMPA-BBB permeability and conformed to the Lipinski's rule of five. Further, compound TM-2 presented precognitive effect on scopolamine-induced memory impairment in vivo assay. Therefore, compound TM-2 might be a promising multifunctional hit compound for the treatment of AD, and the further structure optimization are in progress.
Keywords: Alzheimer's disease; Antioxidant agents; Aβ aggregation inhibitors; Biometals chelator; BuChE inhibitors; Chalcone derivatives; Monoamine oxidase B inhibitor; Multifunctional agents; Neuroprotective effect; Precognitive effect.
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