Ren Bo, Guo Cong, Liu Run-Ze, Bian Zhao-Yuan, Liu Rong-Chun, Huang Lan-Fang, Tang Jiang-Jiang
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China.
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China.
Eur J Med Chem. 2022 Jan 15;228:114031. doi: 10.1016/j.ejmech.2021.114031. Epub 2021 Dec 1.
Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC value of 0.57 μM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on HO-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 μM, as well as selectively metal chelating properties via chelating Cu. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.
阿尔茨海默病（AD）具有复杂的发病机制。如今，多靶点药物被认为有潜力通过同时触发功能互补途径中的分子来有效治疗AD。在此，基于针对神经炎症的筛选（约1400种化合物），发现了一种咪唑基苯乙酮肟醚（IOE）作为新的活性化合物。为了获得构效关系，构建了一系列咪唑基苯乙酮肟衍生物，通过单晶确定它们的C=N键为Z构型。这些衍生物表现出潜在的多功能神经保护作用，包括抗神经炎症、抗氧化损伤、金属螯合、抑制乙酰胆碱酯酶（AChE）的特性。在这些衍生物中，化合物12i对一氧化氮（NO）生成表现出最有效的抑制活性，EC值为0.57 μM。12i能剂量依赖性地抑制诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的表达，但不改变血红素加氧酶-1（HO-1）蛋白的表达。此外，12i在10 μM时对HO诱导的PC12细胞损伤和铁死亡表现出明显的神经保护作用且无细胞毒性，以及通过螯合铜表现出选择性金属螯合特性。另外，12i在体外对AChE表现出混合型抑制作用。构效关系（SARs）分析表明苯环上的二氧戊环基团和刚性肟酯可提高活性。平行人工膜渗透试验（PAMPA）也证实12i能够穿越血脑屏障（BBB）。总体而言，这是关于咪唑基苯乙酮肟多功能神经保护作用的首次报道，表明这类化合物可能是新型的抗AD多功能药物。
