Synthesis of Pyridine Quinone Methide Precursors and Studies Towards Realkylation of Aged Acetylcholinesterase
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Date
2017-05
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The Ohio State University
Abstract
Acetylcholinesterase (AChE) is an enzyme that rapidly hydrolyzes acetylcholine and functions in the central and peripheral nervous systems. Organophosphorus compounds (OPs) are used as chemical nerve agents and pesticides, and exposure to OPs affects the central nervous system and causes a buildup of acetylcholine in the body by inhibiting acetylcholinesterase (AChE). After exposure to OPs, AChE is initially inhibited for a period of time followed by an aging process. There are known therapeutic oximes for inhibited AChE but no known treatments for aged AChE. Our research focuses on the development of quinone methides and quinone methide precursors that can be used as realkylators of aged AChE. In previous research, quinone methides have been demonstrated to realkylate phosphonates. The goal of this project is to synthesize quinone methide precursors (QMPs) that will allow for realkylation and subsequent reactivation of AChE. Computational studies have shown that aryl and heterocyclic frameworks could potentially be potent realkylators or form quinone methides. Several frameworks have been synthesized through synthetic pathways including nucleophilic substitution, reductive amination, and Mannich reactions. The substituted frameworks were transformed into their respective ammonium and alkyl-ammonium QMP salts. These libraries were exposed to aged AChE and the reactivation was determined using Ellman’s assay. Synthetic efforts and initial screening results will be presented herein.