Synthesis of Quinone Methide Precursors for the Treatment of Organophosphorus Poisoning

Eighteen quinone methide precursors (QMPs) were synthesized to test their efficacy at resurrecting organophosphorus-aged acetylcholinesterase. This library of QMPs is based on a phenol framework, and the alkyl groups were chosen based on promising results from similar QMP libraries. The QMPs were synthesized via two methods. The quinone methide precursors with a cyclic R’ group were synthesized via a Suzuki Coupling reaction. The QMPs with conjugated R’ groups were synthesized via a Wittig reaction. Both synthetic pathways ended with a Mannich reaction which installed one of five different aminomethyl groups

Study of <i>para</i>-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase

Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP–AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed