(from Mercey et al.) The best global reactivation efficiency has been obtained with a linker length of four or five carbon atoms attached on position 6 of the pyridine ring,i.e., for 1b and 1c. Their derivatives show a lower ability to reactivate VX-inhibited hAChE, yet superior to that of 2-PAM. three new compounds reported,1d,1e, and 1h, are more efficient than TMB-4 for reactivation of tabun-inhibited AChE, while 1a and 1i are as efficient as TMB-4. 1b-d are as efficient as obidoxime and TMB-4 toward paraoxon-inhibited AChE
Title: An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice Calas AG, Dias J, Rousseau C, Arboleas M, Touvrey-Loiodice M, Mercey G, Jean L, Renard PY, Nachon F Ref: Chemico-Biological Interactions, 267:11, 2017 : PubMed
Organophosphorus nerve agents, like VX, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). AChE inhibited by VX can be reactivated using powerful nucleophilic molecules, most commonly oximes, which are one major component of the emergency treatment in case of nerve agent intoxication. We present here a comparative in vivo study on Swiss mice of four reactivators: HI-6, pralidoxime and two uncharged derivatives of 3-hydroxy-2-pyridinaldoxime that should more easily cross the blood-brain barrier and display a significant central nervous system activity. The reactivability kinetic profile of the oximes is established following intraperitoneal injection in healthy mice, using an original and fast enzymatic method based on the reactivation potential of oxime-containing plasma samples. HI-6 displays the highest reactivation potential whatever the conditions, followed by pralidoxime and the two non quaternary reactivators at the dose of 50 mg/kg bw. But these three last reactivators display equivalent reactivation potential at the same dose of 100 mumol/kg bw. Maximal reactivation potential closely correlates to surviving test results of VX intoxicated mice.
Pyridinium and bis-pyridinium aldoximes are used as antidotes to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus nerve agents. Herein, we described a series of nine nonquaternary phenyltetrahydroisoquinoline-pyridinaldoxime conjugates more efficient than or as efficient as pyridinium oximes to reactivate VX-, tabun- and ethyl paraoxon-inhibited human AChE. This study explores the structure-activity relationships of this new family of reactivators and shows that 1b-d are uncharged hAChE reactivators with a broad spectrum.
