Organophosphorus (OP) agents are responsible for the inhibition of the enzyme acetylcholinesterase (AChE) which is found in erythrocytes, brain synapses, and neuromuscular junctions. AChE contains a catalytic triad of serine-histidine-glutamate residues located within the enzyme active site. While AChE is responsible for the hydrolysis of the neurotransmitter acetylcholine, OP compounds are also covalent inhibitors of AChE. As such, various OP compounds have been used as pesticides in agriculture. If sufficient AChE is inactivated, then acetylcholine will accumulate and can lead to serious and adverse health effects, and even eventual death by a variety of medical consequences depending on the route of exposure. Moreover, after a variable period of time has passed, and for a time that is dependent on the structure of the OP compound, AChE can undergo an aging process, resulting in a different structural variant of the active site at the catalytic serine residue. To date, all approved medical countermeasures are unable to recover any activity from the OP-aged form, therefore rendering them useless once a certain time threshold has occurred. Our research team has developed a diverse library of compounds known as quinone methide precursors (QMPs) for which some members have been shown to be effective in converting the OP-aged AChE back to the native, and active, AChE through a process known as “resurrection”. Our synthetic design of the QMPs is based on the optimization of the of amine leaving groups and aryl frameworks, in addition to various substituents used to modify the electronic effects of the system. Indeed, we have developed many QMP-based chemical libraries as we explore the structure and activity relationships for these compounds, and in this presentation, using many different OP compounds, we will discuss the synthetic approaches to substituted alkoxyphenol QMPs as well as the <i>in vitro</i> results from reactivation of OP-inhibited and resurrection of OP-aged AChE.

Preparation and evaluation of quinone methide precursors to reactivate inhibited and resurrect aged acetylcholinesterase after exposure to organophosphorus compounds

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