Development of New Reactivators of Tabun Inhibited Acetylcholinesterase and the Evaluation of Their Efficacy by in Vitro and in Vivo Methods

Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates by its chemical structure and by the fact that tabun-inhibited acetylcholinesterase is extraordinarily difficult to reactivate. The antidotal treatment of tabun acute poisonings still represents a serious problem and the development of new, more effective AChE reactivators to achieve the satisfactorily effective antidotal treatment of acute poisonings with tabun still represents very important goal. Since 2003, we have prepared around 200 new AChE reactivators. Their potency to reactivate tabun-inhibited acetylcholinesterase has been subsequently evaluated using our in vitro screening test. Afterwards, promising compounds were selected and kinetic parameters and reactivation constants were determined. Then, the best reactivators were subjected to the in vivo studies (toxicity test, the evaluation of therapeutical, reactivating and neuroprotective efficacy). According to the results obtained, all new oximes tested in vivo (K027, K048, K074, K075) were found to be relatively effective to eliminate acute lethal toxic effects in tabun poisoned mice and reactivate tabun-inhibited acetylcholinesterase in rats poisoned with tabun. In addition, newly developed oximes (K027, K048, K074, K075) combined with atropine seem to be sufficiently effective antidotes for a significant decrease in tabun-induced neurotoxicity in the case of sublethal poisonings of rats although they are not able to eliminate tabun-induced neurotoxicity completely. Our results also confirm that the reactivating efficacy of oximes evaluated by the methods in vitro correlates not only with the potency of oximes in reactivating tabun-inhibited acetylcholinesterase in vivo but also with the ability of oximes to protect rats poisoned with supralethal doses of tabun.