Abstract：
In this paper, we developed a series of piperic acid (PA) analogs with the aim of overcoming the limitations associated with the natural products for the management of Alzheimer\'s disease (AD). A comprehensive SAR study was performed to enhance cholinesterase inhibition of PA. The acetylcholinesterase inhibition and its kinetic data suggested 6j as the lead molecule (AChE IC50 = 2.13 ± 0.015 µM, BChE = 28.19 ± 0.20%), in comparison to PA (AChE = 7.14 ± 0.98%) which was further selected for various biological studies in AD models. 6j, exhibited interaction with the peripheral anionic site of AChE, BBB permeability (Pe = 7.98), and antioxidant property (% radical scavenging activity = 35.41 ± 1.09, 2.43 ± 1.65, for 6j and PA at 20 M μ , respectively). The result from the metal chelation study suggests that 6j did not effectively chelate iron. The molecular modeling studies suggested that 6j could effectively interact with Ser293, Phe295, Arg296, and Tyr34 of AChE. In the cell-based cytotoxicity studies, 6j exhibited cytocompatibility at the different tested concentrations. The acute toxicity data on mice suggested that compound 6j had no renal and hepatotoxicity at 500 mg/kg. Moreover, 6j could effectively reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice. The above results strongly suggest that compound 6j may act as a novel multi-targeted lead for AD therapy.
摘要：
在本文中,我们开发了一系列胡椒酸（PA）类似物，旨在克服与治疗阿尔茨海默病（AD）的天然产物相关的局限性。进行了全面的SAR研究以增强PA的胆碱酯酶抑制作用。乙酰胆碱酯酶抑制作用及其动力学数据表明6j是前导分子（AChEIC50=2.13±0.015µM，BChE=28.19±0.20%),与PA（AChE=7.14±0.98％）相比，后者被进一步选择用于AD模型中的各种生物学研究。6j,表现出与AChE外周阴离子位点的相互作用，BBB渗透率（Pe=7.98），和抗氧化性能（自由基清除活性%=35.41±1.09，2.43±1.65，对于6j和PA在20M[配方：见正文]，分别)。金属螯合研究的结果表明6j不能有效螯合铁。分子建模研究表明，6j可以有效地与AChE的Ser293，Phe295，Arg296和Tyr34相互作用。在基于细胞的细胞毒性研究中，6j在不同的测试浓度下表现出细胞相容性。小鼠的急性毒性数据表明化合物6j在500mg/kg时没有肾和肝毒性。此外，6j可以通过改善小鼠的空间和认知记忆来有效逆转东pol碱引起的健忘症。上述结果强烈提示化合物6j可作为AD治疗的新型多靶向导联。
