title: Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer's Disease.
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 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland. mike_jone5@hotmail.com.
authors.forename: Mike
authors.initials: M
authors.lastname: Jones
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland. wangju@tcd.ie.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland. s.harmon@redxpharma.com.
authors.forename: Shona
authors.initials: S
authors.lastname: Harmon
authors.affiliation: Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany. Beata.Kling@chemie.uni-regensburg.de.
authors.forename: Beata
authors.initials: B
authors.lastname: Kling
authors.affiliation: Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany. Joerg.Heilmann@chemie.uni-regensburg.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland. gilmerjf@tcd.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D004952:Esters; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; antioxidant; cholinesterase inhibitor; hybrid; neuroprotection