Development of novel chalcone derivatives as multifunctional agents for the treatment of Alzheimer’s disease

To develop multifunctional agents for the treatment of Alzheimer’s disease (AD), a series of novel chalcone derivatives was developed as the multitarget-directed ligands. Their MAOs inhibitory activities, anti-inflammation properties and neuroprotective effects were evaluated in vitro. The results showed that most of the synthetic compounds exhibited good selective MAO-B inhibitory activity. Among them, compound 3i exhibited the best MAO-B inhibitory potency with IC₅₀ values of 0.092 μM, and the molecular docking provide possible mechanism for its high MAO-B inhibitory potency. Compound 3i also significantly inhibited self-induced Aβ_1-42 aggregation. Moreover, compound 3i showed significant anti-inflammation property and good neuroprotective effects on Glu-/Aβ_25-35-induced PC12 cell injury. Furthermore, compound 3i showed favorable ADME properties. Thus, the results suggest that compound 3i was a promising multifunctional agent against AD.