Specification of the Structure of Oximes Able to Reactivate Tabun‐Inhibited Acetylcholinesterase

Abstract

The efficacy of various oximes to reactivate acetylcholinesterase phosphorylated by tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) was tested by in vitro and in vivo methods. The oximes commonly used for the treatment of acute poisonings with highly toxic organophosphates appeared to be almost ineffective (HI-6, pralidoxime, methoxime) or just slightly effective (obidoxime) against tabun. On the other hand, trimedoxime seemed to be a significantly more efficacious reactivator than the others in the case of tabun poisonings. In vitro, the concentration of trimedoxime corresponding to 1.0 mmol/l was able to reach 50% reactivation of tabun-inhibited brain acetylcholinesterase. Higher reactivating potency of trimedoxime in comparison with the other commonly used oximes was demonstrated by in vivo method, too. In addition, other structural analogues of trimedoxime were found to be efficacious in counteracting tabun-induced acetylcholinesterase inhibition although not as efficacious as trimedoxime itself. Some effective acetylcholinesterase reactivators were characterised by dissociation constant of enzyme-reactivator complex as well as enzyme-inhibitor-reactivator complex and by rate constant of reactivation.

Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes

“…For example, pralidoxime is unable to reactivate tabun-inhibited and cyclosarin-inhibited AChE in vitro and in vivo [6][7][8]. Similar results were obtained for obidoxime.…”

“…The chemical structure of AChE reactivators affects their ability to reactivate AChE inhibited by nerve agents [6,8]. Some of the most important moieties include the presence of the oxime group, the presence of quaternary nitrogen, and the appropriate length of the connection chain between both quaternary nitrogens [27].…”

“…Currently the most promising AChE reactivator, oxime HI-6, is the strongest in vitro and in vivo reactivator against almost all of the nerve agents [5,10]. Unfortunately, it has no potency to reactivate tabuninhibited AChE [6,7]. Therefore, the replacement of currently used AChE reactivators with new and more effective oximes is a long-standing goal for the treatment of poisonings associated with highly toxic OPCs.…”

Synthesis of monooxime-monocarbamoyl bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against tabun- and paraoxon-inhibited acetylcholinesterase

“…The aged AChE is inhibited completely and can not be reactivated. One of the most resistant inhibitions is caused by the nerve agent tabun (GA) [18]. Although the structural basis for resistance of tabun conjugates is unknown, the crystal structures of murine AChE showed that non-aged tabun conjugate induces structural changes in H447 and its hydrogen bonds [16,19].…”

Reactivation Potency of New Group of Acetylcholinesterase Reactivators and Their Comparison with Currently Available Oximes

“…For example, soman inhibited AChE is after several minutes not treatable due to the aging (dealkylation) (5,6). Also AChE inhibited by tabun and cyclosarin is difficult to reactivate due to the lone electron pair at the amide group (tabun) or presence of bulky cyclohexyl group (cyclosarin), respectively (1,7) Currently the most promising AChE reactivator -oxime HI-6 -is not able to reactivate tabun or pesticide-inhibited AChE (1,14).…”