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Pralidoxime analogues as efficient reactivators of ChE inhibited by OP nerve agents and pesticides

The covalent inhibition of cholinesterases (ChE) with organophosphates (OPs) requires immediate treatment mostly based on oximes as reactivators of acetylcholinesterase (AChE). A downfall of this well-known treatment is its inapplicability for the reactivation of butyrylcholesterase (BChE) or targeted AChE in brain due to the poor blood brain barrier (BBB) penetration of the oximes. Thus new oximes were synthesized, referring to standard oxime pralidoxime (2-PAM), with permanently charged pyridinium rings, but with longer aliphatic linkers which improved their ability to penetrate the BBB regarding in silico results. We singled out three analogs of 2-PAM for which both enzymes had moderate affinity, with a 2- to 14- fold higher binding proficiency of AChE than BChE. In a previous study, certain pyridinium oximes were identified with a significantly improved in vitro reactivation potential for tabun inhibited- AChE. So in this research we wanted to test the reactivation ability, not only for ChE inhibited by nerve agents but also by organophosphorus pesticides that are analogs of tabun, metamidophos and fenamiphos. From several combinations of an oxime and the OP-ChE conjugate, 2-PAM analogs have shown the highest reactivation efficiency for cyclosarin, with a 300-fold higher overall kinetic reactivation rate for BChE than standard oxime. Moreover, the reactivation potency of cyclosarin- inhibited AChE was up to 90% for one oxime. With regard to ChE inhibited with pesticides, the acquired results were slightly better than for 2- PAM, with the highest reactivation of 60% recorded for fenamifos-inhibited BChE. Taking into account the reactivation efficacy for cyclosarin exposure, oximes were also evaluated in ex vivo conditions together with exogenous BChE. The obtained results demonstrated up to 80% of restored phosphonylated cholinesterase activity within a short time. Considering our results, we identified three efficient reactivators of phosphylated BChE that, due to a cumulative capacity to reactivate both AChE and BChE, possess the potential for further evaluation in OP bioscavenging.

Organophosphorus compounds, acetylcholinesterase, butyrylcholesterase, pyridinium oximes, bioscavenging

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