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Unexpected AChE inhibitory activity of (2E)α,β-unsaturated fatty acids
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2018-09-11 , DOI: 10.1016/j.bmcl.2018.09.013
Anne Loesche , Jana Wiemann , Zayan Al Halabi , Julia Karasch , Wolfgang Sippl , René Csuk

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 IC50 = 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 Ki = 1.51 ± 0.09 M and Ki′ = 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.



中文翻译:

(2 E)α,β-不饱和脂肪酸的意外的AChE抑制活性

制备了一个小的(E)α,β-不饱和脂肪酸文库,并对20种链长不同的饱和和单不饱和脂肪酸进行了Ellman分析,以确定它们充当AChE或BChE抑制剂的能力。虽然这些化合物只是BChE的非常弱的抑制剂,但有7个分子是AChE的抑制剂,IC 50  = 4.3-12.8 M,其中三个是该酶的重要抑制剂。结果表明,反式2-单不饱和脂肪酸比其饱和类似物是更好的AChE抑制剂。此外,筛选结果表明链长对于获得抑制功效至关重要。对于(2 E)二十碳烯酸(图14)显示了抑制常数K i  = 1.51±0.09 M和K i '= 7.15±0.55M。所有测试的化合物均为竞争性主要成分的混合型抑制剂。分子模型计算表明活性/非活性化合物与酶AChE和BChE的结合方式不同。

更新日期:2018-09-11
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