Organophosphorus compounds (OPs) such as tabun, sarin and soman are used as chemical warfare nerve agents. The advancements of chemical warfare agents used for military tactics exceed the research to inhibit the effects of the nerve gases. The demand to study OP nerve agents is crucial because of the damaging effects to people, the commercial availability, and even the stockpiles in countries. Exposure to OPs affects the central nervous system and causes a buildup of acetylcholine in the body by inhibiting acetylcholinesterase (AChE). The AChE is initially inhibited followed by an aging process. There are known therapeutic oximes for inhibited AChE, pyridinium oximes; however, there are no known treatments for aged AChE. We are developing a library quinone methide precursors (QMPs) to be used as potential re-alkylators. These QMPs can be used to potentially re-alkylate the aged OP-AChE complex followed by reactivation. This research is vital to enhance the pharmaceutical measures and further inspire more research done to medically counteract the aging process. Several frameworks were synthesized through synthetic routes including nucleophilic substitution, reductive amination, and Mannich reactions. We will present the synthesis of a small library of pyridine QMP frameworks and the screening of these compounds as re-alkylators and re-activators of both the inhibited and aged AChE (electric eel and human).

Synthesis and evaluation of pyridine based quinone methide precursors for aged acetylcholine esterase reactivation

255th National Meeting (2018)

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