Cao_2021_Bioorg.Med.Chem_35_116074

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 x 10(-5) and 6.16 x 10(-4) microM, respectively), good MAO-B inhibitory activity (IC(50) = 5.88 microM) and high antioxidant activity (ORAC =2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu(2+)-induced Abeta(1-42) aggregation inhibitory potency, disaggregation ability on Abeta(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.