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Molecules 2016, 21(4), 440; doi:10.3390/molecules21040440

Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer’s Disease

School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland
Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany
Author to whom correspondence should be addressed.
Academic Editors: Michael Decker and Diego Muñoz-Torrero
Received: 2 March 2016 / Revised: 21 March 2016 / Accepted: 23 March 2016 / Published: 1 April 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
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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. View Full-Text
Keywords: neuroprotection; Alzheimer’s disease; antioxidant; cholinesterase inhibitor; hybrid neuroprotection; Alzheimer’s disease; antioxidant; cholinesterase inhibitor; hybrid

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Jones, M.; Wang, J.; Harmon, S.; Kling, B.; Heilmann, J.; Gilmer, J.F. Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer’s Disease. Molecules 2016, 21, 440.

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