Qualitative and quantitative structure activity relationships for the inhibitory effects of cationic head groups, functionalised side chains and anions of ionic liquids on acetylcholinesterase
Qualitative and quantitative structure activity relationships for the inhibitory effects of cationic head groups, functionalised side chains and anions of ionic liquids on acetylcholinesterase
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DOI：
10.1039/b712109a
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发表时间：
2008-01-01
期刊：
影响因子：
9.8
通讯作者：
Ranke, Johannes
中科院分区：
文献类型：
--
作者：
Arning, Juergen;Stolte, Stefan;Ranke, Johannes
为了更深入地了解离子液体对人类和环境的潜在危害，使用乙酰胆碱酯酶（AchE）抑制筛选试验来鉴定毒基团亚结构和介导酶抑制的相互作用电位。带正电的氮原子、广泛离域的芳香系统以及连接到阳离子头基的侧链的亲脂性可以被确定为与酶活性位点结合的关键结构元件。就此而言，二甲氨基吡啶鎓、喹啉鎓和吡啶鎓头基对酶表现出非常强的抑制潜力，IC50值约为10μM。相反，极性和非芳香族吗啉鎓头基对酶活性的抑制很弱，IC50值>500μM。在烷基侧链中引入极性羟基、醚或腈官能团被证明是有效的。结构改变以将相应的离子液体转移到较低的抑制电位。支持这一事实的是，对于一系列咪唑鎓阳离子，通过 IC50 的对数与 HPLC 得出的亲脂性参数 k(0) 的对数的线性回归建立了 QSAR 相关性。此外，还测试了通常用作离子液体抗衡离子的广泛阴离子种类（无机、有机和复合硼酸盐阴离子），绝大多数对 AchE 没有影响。只有易于水解的氟化物和含氟阴离子物质才能被鉴定为 AchE 抑制剂。
To contribute to a deeper insight into the hazard potential of ionic liquids to humans and the environment, an acetylcholinesterase (AchE) inhibition screening assay was used to identify toxicophore substructures and interaction potentials mediating enzyme inhibition.The positively charged nitrogen atom, a widely delocalised aromatic system, and the lipophilicity of the side chains connected to the cationic head groups can be identified as the key structural elements in binding to the enzymes active site. With respect to this, the dimethylaminopyridinium, the quinolinium and the pyridinium head groups exhibit a very strong inhibitory potential to the enzyme with IC50 values around 10 mu M. In contrast, the polar and non-aromatic morpholinium head group is found to be only weakly inhibiting to the enzyme activity, with IC50 values > 500 mu M.The introduction of polar hydroxy, ether or nitrile functions into the alkyl side chain is shown to be a potent structural alteration to shift the corresponding ionic liquids to a lower inhibitory potential. Supporting this fact, for a series of imidazolium cations, a QSAR correlation was set up by the linear regression of the log IC50 versus the logarithm of the HPLC-derived lipophilicity parameter k(0).Additionally, a broad set of anion species (inorganic, organic and complex borate anions), commonly used as ionic liquid counterions, was tested and the vast majority exhibited no effect on AchE. Only the fluoride and fluoride containing anion species which readily undergo hydrolytic cleavage can be identified to act as AchE inhibitors.