Loesche Anne, Wiemann Jana, Al Halabi Zayan, Karasch Julia, Sippl Wolfgang, Csuk René
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.
Martin-Luther-University Halle-Wittenberg, Institute of Pharmacy, Wolfgang-Langenbeck-Str. 4, D-06120 Halle (Saale), Germany.
Bioorg Med Chem Lett. 2018 Nov 1;28(20):3315-3319. doi: 10.1016/j.bmcl.2018.09.013. Epub 2018 Sep 11.
A small library of (E) α,β-unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman's assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC = 4.3-12.8 M with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs. Furthermore, the screening results indicate that the chain length is crucial for obtaining an inhibitory efficacy. The best results were obtained for (2E) eicosenoic acid (14) showing inhibition constants K = 1.51 ± 0.09 M and K' = 7.15 ± 0.55 M. All tested compounds were mixed-type inhibitors with a dominating competitive part. Molecular modelling calculations indicate a different binding mode of active/inactive compounds for the enzymes AChE and BChE.
制备了一个小型的（E）α,β-不饱和脂肪酸文库，并对20种不同链长的饱和及单不饱和脂肪酸进行了埃尔曼检测，以确定它们作为乙酰胆碱酯酶（AChE）或丁酰胆碱酯酶（BChE）抑制剂的能力。虽然这些化合物对BChE只是非常弱的抑制剂，但有7种分子是AChE的抑制剂，其半数抑制浓度（IC）为4.3 - 12.8 μM，其中3种是该酶的显著抑制剂。结果表明，反式2-单不饱和脂肪酸作为AChE抑制剂比其饱和类似物效果更好。此外，筛选结果表明链长对于获得抑制效果至关重要。（2E）二十碳烯酸（14）的抑制常数K = 1.51 ± 0.09 μM和K' = 7.15 ± 0.55 μM，得到了最佳结果。所有测试化合物均为混合型抑制剂，且以竞争性部分为主导。分子模拟计算表明，活性/非活性化合物与AChE和BChE酶的结合模式不同。
