Structure-Activity Relationships for Substituted 3-Pyridinol Mannich Bases in the Resurrection of Methylphosphonate-Aged Human Acetylcholinesterase

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Date

2019-03

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Abstract

Methylphosphonate chemical nerve agents have been used throughout history for a number of nefarious purposes, resulting in the deaths of thousands. Methylphosphonate nerve agents belong to a class of organophosphorus (OP) molecules that inhibit the function of acetylcholinesterase (AChE). The inhibition of AChE leads to a cholinergic crisis that if not treated results in death. Therapeutics have been developed to treat the inhibited state of AChE; however, a spontaneous aging reaction competes with this reactivation and leaves the enzyme in a state that is recalcitrant to all known therapeutics. Herein, we have developed a number of compounds that can effectively recover the activity of the aged form of the enzyme, resurrection, and investigated the structural features that lead to increases in efficacy. In total, 20 novel compounds were determined to be capable of resurrecting aged-human AChE with the most efficient compound recovering nearly 15% of aged AChE activity over 24 hours.

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Mathematical and Physical Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)

Keywords

Acetylcholinesterase, Resurrection, Quinone Methide Precursor, Organophosphorus Nerve Agent

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