Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters () were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, derivatives − were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that ()-oxime ether (derivative ) had stronger anti-neuroinflammatory and neuroprotective ability than ()-congener. Then, derivatives − were synthesized based on target-directed ligands and activity-based groups hybridization strategy. anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative exhibited the strongest inhibitory activity on NO production with EC value of 0.49 μM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that could inhibit the release of pro-inflammatory factors PGE and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, can dose-dependently inhibit acetylcholinesterase (AChE) and Aβ aggregation. Moreover, the selected nuclide [F]-labeled was synthesized to explore its biodistribution by micro-PET/CT, of which can penetrate the blood-brain barrier (BBB). These results shed light on the potential of as a new multifunctional candidate for AD treatment.

中文翻译：

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咪唑基苯乙酮肟衍生物的设计、合成和生物学评价作为治疗阿尔茨海默病的新型脑渗透剂


随着人口老龄化，阿尔茨海默病（AD，又称痴呆）已成为严重的全球健康问题，而神经炎症是大脑认知障碍的根本原因。目前，开发多靶点抗AD药物被认为是一种有效的途径。咪唑基苯乙酮肟醚或酯 () 是多功能药物，具有神经炎症抑制、金属螯合、抗氧化和神经保护特性，可对抗阿尔茨海默病。本研究通过肟和咪唑基团的结构修饰得到衍生物−，SARs表明()-肟醚（衍生物）比()-同系物具有更强的抗神经炎症和神经保护能力。然后，基于靶向配体和基于活性的基团杂交策略合成衍生物。抗AD活性筛选显示，一些衍生物表现出潜在的多功能作用，其中衍生物对NO产生的抑制活性最强，EC值为0.49 μM，并对6-OHDA诱导的细胞损伤和RSL3诱导的铁死亡具有神经保护作用。抗神经炎症机制表明，可抑制促炎因子PGE和TNF-α的释放，下调iNOS和COX-2蛋白的表达，促进BV-2细胞从促炎M1表型极化抗炎 M2 表型。此外，还能剂量依赖性地抑制乙酰胆碱酯酶（AChE）和Aβ聚集。此外，合成了所选的[F]标记核素，并通过微型PET/CT探索其生物分布，其可以穿透血脑屏障（BBB）。 这些结果揭示了作为 AD 治疗的新型多功能候选药物的潜力。