engleski

Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents

The cholinesterase reactivators (so called “oximes”) are used as causal antidotes in case of organophosphorus intoxications. The oxime moiety in the form of oximate anion is crucial factor for effective reactivation of cholinesterases. In 2018, the chlorinated oximes were introduced to increase the formation of oximate formation and thus for effective reactivation [1]. The chlorinated oximes were found to be highly efficient reactivators of phosphylated acetylcholinesterase when compared to pralidoxime and asoxime (HI-6) [1]. Moreover, the chlorinated oximes were found to be efficient reactivators of phosphylated butyrylcholinesterase when compared to pralidoxime and asoxime [2]. More recently, the fluorinated oximes (Fig. 1) were prepared, thoroughly evaluated and compared to chlorinated ones [3]. Their oximate formation was found better to chlorinated oximes, although particular instability was found in a buffered environment. Mono-fluorinated oximes showed comparable reactivation to non-halogenated (except asoxime) and mono-chlorinated oximes in case of AChE inhibited by sarin, cyclosarin, VX, and tabun, but were less efficient than di-chlorinated ones. The same trend was observed in the reactivation of inhibited BChE. The further in vivo administration of highly efficient reactivator and the most promising analogue, 3, 5- dichloro-bispyridinium oxime with trimethylene linker, provided significant protection of mice exposed to sarin and cyclosarin. [1]. T. Zorbaz, D. Malinak, et al. J. Med. Chem., 61, 10753-10766 [2]. T. Zorbaz, D. Malinak, et al. Chem Biol Interact, 307, 16-20. [3]. T. Zorbaz, D. Malinak, et al. submitted.

organophosphates, acetylcholinesterase, butyrylcholinesterase, pyridinium oximes

nije evidentirano