Novel selective butyrylcholinesterase inhibitors incorporating antioxidant functionalities as potential bimodal therapeutics for Alzheimer’s Disease

URN to cite this document:

urn:nbn:de:bvb:355-epub-415653 Copy

DOI to cite this document:

10.5283/epub.41565 Copy

Jones, Mike ; Wang, Jun ; Harmon, S. ; Kling, Beata ; Heilmann, Jörg

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Date of publication of this fulltext: 12 Feb 2020 13:00

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Details

Item type:	Article
Journal or Publication Title:	Molecules
Publisher:	MDPI AG
Place of Publication:	BASEL
Volume:	21
Page Range:	p. 440
Date:	2016
Institutions:	Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Biology (Prof. Heilmann)
Identification Number:	Value Type 10.3390/molecules21040440 DOI
Keywords:	FERULIC ACID HYBRIDS; LIPOIC ACID; OXIDATIVE STRESS; CHOLINESTERASE-INHIBITORS; NEURONAL CELLS; ACETYLCHOLINESTERASE; FLAVONOIDS; DESIGN; MOUSE; ESTER; neuroprotection; Alzheimer's disease; antioxidant; cholinesterase inhibitor; hybrid
Dewey Decimal Classification:	500 Science > 540 Chemistry & allied sciences
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	41565

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Abstract

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 ...

Abstract

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 mu M 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 mu M. 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.

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Metadata last modified: 25 Nov 2020 16:53

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