Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC ₅₀  = 9.18 × 10 ^-5 and 6.16 × 10 ^-4 μM, respectively), good MAO-B inhibitory activity (IC ₅₀  = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu ²⁺ -induced Aβ _1-42 aggregation inhibitory potency, disaggregation ability on Aβ _1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.
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