Synthesis and Evaluation of Benzylsulfide Quinone Methide Precursors for the Treatment of Organophosphorus Exposure
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Date
2025-05
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The Ohio State University
Abstract
Organophosphorus (OP) compounds are a class of toxic compounds which are used throughout the world as pesticides, and unfortunately also for terrorism. These compounds exert their toxicity by covalently inhibiting the enzyme acetylcholinesterase (AChE). AChE is responsible for hydrolysis of the neurotransmitter acetylcholine (ACh). OP compounds covalently inhibit the catalytic serine responsible for performing the normal hydrolysis of ACh. When hydrolysis of ACh is disrupted, the neurotransmitter builds up within synapses, leading to an overstimulation of nerve signaling and a set of symptoms known as cholinergic crisis. These symptoms affect cardiovascular, respiratory, and central nervous system functions which, if not treated appropriately or quickly, eventually leads to death.
Current treatments for OP poisoning include oximes which can reverse the effects of some OP exposure, a process termed reactivation of the OP-inhibited forms. However, oximes are limited in their efficacy against the many different OP-inhibited forms of AChE. Furthermore, following OP inhibition, a secondary process can occur, called aging, where a spontaneous O-dealkylation occurs. Oximes are ineffective at recovering (resurrecting) native activity from the OP-aged forms of AChE. These gaps in efficacy reveal the need for novel therapeutics that can perform both reactivation of OP-inhibited and resurrection of OP-aged AChE. Previous work from our lab has shown the ability of quinone methide precursors (QMPs) to perform resurrection of OP-aged AChE and reactivation of OP-inhibited AChE. In this thesis, we will also evaluate another cholinesterase enzyme, butyrylcholinesterase (BChE).
From our previous work, it has been shown that phenol and pyridin-3-ol QMPs with different substitutions at the 4-position (phenol) or analogous 6-position (pyridin-3-ol) have proven effective in reactivation as well as some resurrection of phosphylated AChE, but optimization is needed to fill gaps for broad-scope efficacy. In this work, we demonstrate the synthesis of a chemical library of benzylsulfide QMPs with varying electronic properties on the peripheral benzylsulfide ring. Substituents were chosen to increase the binding affinity of the QMPs and to gain insight into the electronic effects of the peripheral ring and binding, along with structure-activity relationships. This library of 100 QMPs were evaluated against 6 OP-inhibited and 2 OP-aged forms of AChE and BChE. Many QMP compounds showed broad-scope reactivation of AChE and BChE, with therapeutics capable of an impressive >20% reactivation of OEt-, OiPr-, OCy-, (OEt)(NMe2)- and EP-inhibited forms of both AChE and BChE after 1 hour of incubation and with a concentration of 250 µM. Analysis of structure-activity trends reveals that benzylsulfide QMPs with strong electron-withdrawing substituents provide the most efficacy against all OP-inhibited forms. We identify 13 as the lead framework that has the most broad-scope efficacy for OP-inhibited AChE and BChE reactivation, noting there is high specificity for the amine substituent on the QMP between AChE and BChE. Unfortunately, low percentages of resurrection of OP-aged forms were observed, but the demonstration of resurrection indicates these benzylsulfide compounds are promising leads to optimize for potentially elucidating more success in resurrection.
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Keywords
organic synthesis, AChE, BChE, organophosphorus