Discovery of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones as balanced multifunctional agents against Alzheimer's disease

Based on previous work, a series of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones derivatives were identified as potential multifunctional therapeutic agents for Alzheimer's disease. Biological evaluation exhibited that these derivatives had great performance against MAO-B, Aβ_1-42 aggregation, oxidative stress and metal ion dyshomeostasis. Among them, 10x was selected as the optimal agent for its excellent MAO-B inhibitory activity (IC₅₀ = 0.41 μM, SI > 24.4), good antioxidant activity (1.16 Trolox equivalent) and anti-Aβ aggregation activity (56.03% and 57.51% for inhibition of self- and Cu²⁺-induced Aβ_1-42 aggregation; 81.91% and 82.40% for disaggregation of self- and Cu²⁺-induced Aβ_1-42 fibrils at 25.0 μM). Besides, 10x also exhibited obvious metal-ion chelating ability, anti-neuroinflammation (NO, TNF-α), neuroprotective activity and BBB permeability. More importantly, in vivo behavioral assessment demonstrated 10x could remarkably improve the memory and cognitive impairment in Aβ_1-42 induced AD mice model. Overall, these test results indicated 10x could serve as a balanced multifunctional anti-AD agent and deserved further research.

5-(2-Hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones; Alzheimer's disease; Anti-neuroinflammation; Antioxidant; Aβ aggregation inhibitors; MAO-B selective inhibitors; Multifunctional anti-AD agents.