探索新型邻苯二甲酰亚胺-羟基吡啶酮衍生物作为治疗阿尔茨海默病的多功能药物候选物。
Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease.
机构信息
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
出版信息
Bioorg Chem. 2023 Dec;141:106817. doi: 10.1016/j.bioorg.2023.106817. Epub 2023 Sep 9.
A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe = 17.07-19.52), in addition to potent inhibition of human monoamine oxidase B (hMAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe value of 18.51, along with selective hMAO-B inhibitory activity (IC = 0.79 ± 0.05 μM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 μM. Additionally, compound 11n displayed a cytoprotective effect against HO-induced oxidative damage. Moreover, compound 11n exhibited ideal blood-brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.
我们设计并评估了一系列新型的邻苯二甲酰亚胺-羟基吡啶酮衍生物，作为有潜力的抗阿尔茨海默病（AD）药物。生物活性测试表明，所有化合物均表现出很强的铁离子螯合活性（pFe = 17.07-19.52），此外对人单胺氧化酶 B（hMAO-B）具有很强的抑制作用。化合物 11n 是最有效的抗 AD 先导化合物，pFe 值为 18.51，对 hMAO-B 具有选择性抑制活性（IC = 0.79 ± 0.05 μM，SI > 25.3）。细胞毒性试验结果表明，化合物 11n 在 50 μM 时对 PC12 细胞系的毒性极弱。此外，化合物 11n 对 HO 诱导的氧化损伤具有保护作用。此外，化合物 11n 在平行人工膜渗透测定（PAMPA）中具有理想的血脑屏障（BBB）渗透性，并显著改善了东莨菪碱诱导的小鼠行为实验中的认知和记忆损伤。总之，这些有利的实验结果表明，化合物 11n 值得进一步研究作为抗 AD 的先导化合物。
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