Organophosphorus (OP) nerve agents are covalent inhibitors of acetylcholinesterase (AChE), an essential enzyme that degrades acetylcholine in the nervous system. Following inhibition by OPs, AChE can undergo a subsequent irreversible aging process in which the OP-AChE adduct is dealkylated, thereby resulting in the accumulation of excess acetylcholine at the neuromuscular junction. Current oximes used to treat the nerve agent-inhibited AChE are ineffective because the aged enzyme is recalcitrant to oxime therapy. Previous studies have shown that quinone methides (QM) could potentially reverse the aging process of AChE through a kinetically favored alkylation of the OP phosphonate. Guided by computational methods, we have designed and synthesized a series of QM precursors and investigated their ability to alkylate a panel of nucleophiles. Mechanistic studies were conducted using GC-MS, LC-MS and NMR spectrophotometric techniques. The most promising QM precursors will be tested for the alkylation of aged AChE

Mechanistic insights into the alkylation reactions of quinone methide precursors: Towards the realkylation of aged acetylcholinesterase after exposure to nerve agents

243rd National Meeting (2012)

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