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Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

机译:双功能酚-胆碱结合物作为抗氧化剂和乙酰胆碱酯酶抑制剂

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Because of the complex cascade of molecular events that can occur in the brain of an Alzheimer’s disease (AD) patient, the therapy of this neurodegenerative disease seems more likely to be achieved by multifunctional drugs. Herein, a new series of dual-targeting ligands have been developed and in vitro bioevaluated. Their architecture is based on conjugating the acetylcholinesterase inhibition and anti-oxidant properties in one molecular entity. Specifically, a series of naturally occurring phenolic acids with recognized anti-oxidant properties (derivatives of caffeic acid, rosmarinic acid, and trolox) have been conjugated with choline to account for the recognition by acetylcholinesterase (AChE). The synthesized hybrid compounds evidenced AChE inhibitory capacity of micromolar range (rationalized by molecular modeling studies) and good antioxidant properties. Their effects on human neuroblastoma cells, previously treated with beta-amyloid peptides and 1-methyl-4-phenylpyridinium ion neurotoxins (to simulate AD and Parkinson’s disease, respectively), also demonstrated a considerable capacity for protection against the cytotoxicity of these stressors.
机译:由于阿尔茨海默氏病(AD)患者的大脑中可能会发生复杂的分子事件,因此,通过多功能药物似乎更可能实现这种神经退行性疾病的治疗。在此,已经开发了一系列新的双重靶向配体并进行了体外生物评价。它们的结构基于在一个分子实体中结合乙酰胆碱酯酶的抑制和抗氧化特性。具体而言,已将一系列具有公认的抗氧化性能的天然酚酸(咖啡酸,迷迭香酸和trolox的衍生物)与胆碱偶联,以说明乙酰胆碱酯酶(AChE)的识别作用。合成的杂合化合物证明了AChE抑制能力在微摩尔范围内(通过分子模型研究合理化)和良好的抗氧化性能。它们对人类神经母细胞瘤细胞的作用,以前用β-淀粉样蛋白肽和1-甲基-4-苯基吡啶鎓离子神经毒素(分别模拟AD和帕金森氏病)进行了治疗,也显示出了保护这些应激源的细胞毒性的强大能力。

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