Knowledge Bank

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 OP compounds have been used as chemical warfare agents as well as pesticides. Without functioning AChE, acetylcholine will accumulate and can lead 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 prior to the aging time frame. If left untreated, aging will occur, which is a dealkylation of the phosphylated serine residue in the active site to form an anionic phosphonate (or phosphate) serine. Aging forms a stable, anionic phosphylated intermediate and that species has been recalcitrant to reactivation by oximes. Thus, there are currently no effective treatments to reverse the aging process. Our research focuses on synthesizing and testing small organic compounds that can hopefully re-alkylate the OP-aged enzyme and enable it to be reactivated by pyridinium oximes. Quinone methide precursors (QMPs) are of particular interest because their structures resemble 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 structures like phosphodiesters, DNA and proteins, so they could potentially realkylate aged AChE as well. Their reactivity can be intensified by the addition of other functional groups to their framework. Many libraries of QMPs have been synthesized, specifically libraries derived from different quinoline and isoquinoline frameworks. The aim is that one of these synthesized derivatives will be the key to realkylating aged AChE efficiently, and eventually lead to the reactivation of the enzyme. I will present multiple synthetic efforts towards the assembly of QMPs, as well as their screening assays with OP-aged AChE.