Investigation of Quinone Methide Precursors as Potential Therapeutics for Organophosphorus-exposed Acetylcholinesterase and Butyrylcholinesterase
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Date
2025-05
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The Ohio State University
Abstract
Organophosphorus (OP) compounds covalently inhibit acetylcholinesterase (AChE), an essential enzyme responsible for the hydrolysis of the neurotransmitter, acetylcholine (ACh). Butyrylcholinesterase (BChE) is a non-essential enzyme that is also inhibited by OP compounds, making it a suitable bioscavenger to protect AChE. When exposed, OP compounds significantly inhibit both AChE and BChE by phosphylating the catalytic serine residue of each respective enzyme, leading to cholinergic crisis and eventually death if not treated. The current treatment for OP exposure consists of an oxime capable of reactivating OP-inhibited AChE. However, current oximes have limited blood-brain permeability, thus limiting their efficacy to treat AChE found predominantly in the central nervous system. Furthermore, the OP-inhibited structure of AChE and BChE can undergo spontaneous O-dealkylation, leading to what is referred to as the aged forms which, for both AChE and BChE, are recalcitrant to oxime recovery. This two-part study seeks to enhance the broad-spectrum recovery of AChE while optimizing the scavenging efficiency of BChE by using quinone methide precursors (QMPs). Previous efforts have identified QMPs as a valuable class of compounds capable of reactivating OP-inhibited AChE and BChE as well as recovering OP-aged AChE in a process termed “resurrection.” Two QMP libraries—benzamide derivatives of 4-amidophenol for AChE and 6-methylpyridin-3-ol for BChE—were evaluated using Ellman’s assays to determine their reactivation and resurrection efficacy. Reactivation kinetics experiments were also conducted to gain further insight on the interaction between the QMP and the OP-inhibited enzymes. Top-performing compounds in the 4-amidophenol library display major design improvements, resulting in noteworthy resurrection capabilities and expanded reactivation efficacy across several OP compounds, including historically difficult pesticide compounds. Moreover, leading compounds from the 6- methylpyridin-3-ol library demonstrate effective reactivation for a wide range of OP-inhibited BChE structures. This library demonstrates superior reactivation efficacy over both oxime controls and across all tested OP-inhibited BChE structures, making significant progress toward achieving pseudo-catalytic protection by BChE.
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Keywords
acetylcholinesterase, butyrylcholinesterase, organophosphorus, reactivation, resurrection