期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 250, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115216
关键词
5-(2-Hydroxyphenyl)-2-phthalide-3( 3H ); pyrazolones; Multifunctional anti -AD agents; A; 3 aggregation inhibitors; MAO -B selective inhibitors; Antioxidant; Anti-neuroinflammation
Based on previous research, novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones derivatives were discovered as potential multifunctional therapeutic agents for Alzheimer's disease. These derivatives showed strong activity against MAO-B, A/31-42 aggregation, oxidative stress, and metal ion dyshomeostasis. Among them, 10x was identified as the most effective agent with excellent MAO-B inhibitory activity, antioxidant activity, and anti-A/3 aggregation activity, as well as significant metal-ion chelating ability, anti-neuroinflammation, and neuroprotective activity. Moreover, in vivo behavioral assessment demonstrated that 10x significantly improved memory and cognitive impairment in a mouse model of AD. Overall, these findings suggest that 10x has the potential to be a balanced multifunctional anti-AD agent and should be further investigated.
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, A/31-42 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 mu M, SI > 24.4), good antioxidant activity (1.16 Trolox equivalent) and anti-A/3 aggregation activity (56.03% and 57.51% for inhibition of self-and Cu2+-induced A/31-42 aggregation; 81.91% and 82.40% for disaggregation of self-and Cu2+-induced A/31-42 fibrils at 25.0 mu M). Besides, 10x also exhibited obvious metal-ion chelating ability, anti-neuroinflammation (NO, TNF-a), neuroprotective activity and BBB permeability. More importantly, in vivo behavioral assessment demonstrated 10x could remarkably improve the memory and cognitive impairment in A/31-42 induced AD mice model. Overall, these test results indicated 10x could serve as a balanced multifunctional anti-AD agent and deserved further research.
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