engleski

Modification of oxime nucleophiles for enhanced reactivation of cholinesterases

The cholinesterase reactivators (so-called "oximes”) are used as causal antidotes in case of organophosphorus intoxications. The effectiveness of the reactivator is strongly dependent on the formation of active nucleophile, the oximate anion [1]. Its formation can be supported by optimizing the physical-chemical properties (i.e. pKa) of the oxime and the decreased pKa should lead to enhanced reactivation of phosphylated cholinesterases. For this reason, the charged chlorinated oximes were introduced and proved to highly effective in vitro for reactivation of acetylcholinesterase [2] and butyrylcholinesterase [3] inhibited by multiple organophosphorus agents. The chlorinated oximes were also proved to be not cytotoxic and effective after in vivo administration. More recently, the charged fluorinated oximes were prepared and thoroughly evaluated with promising reactivation results against multiple organophosphorus agents, although their particular lower stability was found [5]. Finally, further modified halogenated oximes with optimized oximate formation were designed and evaluated on cholinesterases inhibited by nerve agent surrogates. Some modified reactivators were proved to be in vitro effective for reactivation of NEMP, NIMP or NEDPA-inhibited AChE and surprisingly one oxime resulted as excellent reactivator of NEMP and NIMP-inhibited BChE. These promising results make prospects for further detailed investigation of modified oximes nucleophiles. This work was supported by Czech Science Foundation (no. 21- 03000S).

cholinesterases, chlorinated oximes, organophosphates, antidote

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