Organophosphorus (OP) agents are responsible for the inhibition of the enzyme acetylcholinesterase (AChE). AChE is responsible for the hydrolysis of the neurotransmitter acetylcholine. OPs are covalent inhibitors of AChE and have been used as chemical warfare agents as well as pesticides. Without functioning AChE, acetylcholine accumulates and leads to serious adverse health effects, such as vomiting, paralysis, and even eventual death by respiratory failure. The magnitude of the effects and rate of death are determined by the OP’s toxicity. There are known therapeutics, called pyridinium oximes, which can reverse the inhibition and reactivate AChE if administration occurs before aging. If left untreated, aging will occur, which is a dealkylation of the OP that is bound in the active site. Aging causes the OP to form a highly stable, charged alkyl phosphonate. There are currently no effective treatments to reverse the aging process, as aged AChE is unresponsive to reactivation by pyridinium oximes.<br/><br/>Our research focuses on synthesizing and testing small organic compounds that can hopefully re-alkylate the aged enzyme and enable it to be activated by pyridinium oximes. Quinone methide precursors (QMPs) are of particular interest because their structure resembles that of other molecules that are capable of binding to the active site of AChE. Furthermore, QMPs have been shown to have the ability to alkylate DNA, so they could potentially realkylate aged AChE as well. Their reactivity can be intensified by addition of other functional groups to their framework. Many libraries of QMPs have been synthesized, specifically libraries derived from different quinolone and isoquinoline frameworks. The aim is that one of these derivatives synthesized will be the key to realkylating aged AChE efficiently, and eventually lead to the reactivation of the enzyme. We will present multiple synthetic efforts towards the assembly of QMPs and screening assays with aged AChE.

Synthesis of quinone methide precursors as acetylcholinesterase reactivators

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.