Unexpected AChE inhibitory activity of (2E)α, β-unsaturated fatty acids. Issue 20 (1st November 2018)

• Record Type: Journal Article
• Authors: Loesche, Anne; Wiemann, Jana; Al Halabi, Zayan; Karasch, Julia; Sippl, Wolfgang; Csuk, René
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 20(2018)
• Page Start: 3315
• Page End: 3319
• Publication Date: 2018-11-01
• Subjects: Fatty acid derivatives -- Acetylcholinesterase -- Butyrylcholinesterase -- Alzheimer's disease; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.09.013
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Twenty different saturated and mono-unsaturated fatty acids were screened as inhibitors of cholinesterases. Several of them were inhibitors of acetyl- but not of butyrylcholinesterase. Chain length as well as configuration is crucial for obtaining inhibitory activity for AChE inhibition. The best results were obtained for (2E) eicosenoic acid. Fatty acids may play a greater role than assumed in the therapy of chronic diseases such as Alzheimer's disease. Abstract: 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 (2 E ) 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.