Jones Mike, Wang Jun, Harmon Shona, Kling Beata, Heilmann Jörg, Gilmer John F
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany.
Molecules. 2016 Apr 1;21(4):440. doi: 10.3390/molecules21040440.
Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase (BuChE). The hybrid compounds were non-toxic to the murine hippocampal cell line HT-22 and lipoate esters were neuroprotective at 10 and 25 µM when the cells were challenged with glutamate (5 mM) in a similar manner to the positive control quercetin. The benzyl carbamate 7a was a potent inhibitor of BuChE (IC50 150 nM) and it was effective in reducing glutamate toxicity to neuronal cells at >5 µM. Representative compounds exhibited an antioxidant effect in the oxygen radical absorbance capacity assay as the lipoate 7d was not active, whereas the ferulate 8a showed a weak, but significant, activity with 0.635 ± 0.020 Trolox Equivalent.
异山梨醇 -2 -氨基甲酸酯 -5 -芳基酯是高效且极具选择性的丁酰胆碱酯酶抑制剂。本研究的目的是验证以下假设：异山梨醇 -芳基 -5 -酯基团可被抗氧化官能团取代，同时保持抑制剂的效果和选择性。我们成功引入了阿魏酸或硫辛酸基团，从而制备出了高效的丁酰胆碱酯酶（BuChE）选择性抑制剂。这些杂合化合物对小鼠海马细胞系HT -22无毒，并且当细胞以与阳性对照槲皮素类似的方式受到谷氨酸（5 mM）刺激时，硫辛酸酯在10和25 μM浓度下具有神经保护作用。苄基氨基甲酸酯7a是BuChE的强效抑制剂（IC50为150 nM），并且在浓度大于5 μM时能有效降低谷氨酸对神经元细胞的毒性。代表性化合物在氧自由基吸收能力测定中表现出抗氧化作用，因为硫辛酸酯7d无活性，而阿魏酸酯8a表现出较弱但显著的活性，其Trolox当量为0.635±0.020。
