College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
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。
