engleski

New scarfolds of oxime-assisted acetylcholinesterase reactivators for treatment in tabun exposure

The copper-catalysed azide-alkyne cycloaddition reaction enables an efficient and reliable synthesis of libraries of new oximes that were screened for the reactivation activity of tabun-inhibited human acetylcholinesterase (AChE), its mutants, and butyrylcholinesterase (BChE). Fifty-three out of 100 oximes reactivated wild type AChE, but only 14 of them restored its full activity. It appears that an approximate distance equivalent to 8 methylenes between two quaternary nitrogens achieved an optimal level of AChE reactivation. The mutant, Y337A, at the choline binding site was reactivated by more than 80 % with only 13 oximes. The most efficient reactivators of Y337A appeared to be 2PAM analogs, with maximal reactivation rate constants kmax up to 10-times faster than those determined for the most efficient reactivator of AChE wild type. Although introducing an additional mutation into the Y337A choline binding site in double mutant Y337A/F338A reduced the enhancement observed in the Y337A mutant, the most efficient Y337A/F338A reactivators also contained the 8 methylene equivalence between two quaternary nitrogens as found for the wild type. Since all oximes were designed as reactivators of phosphorylated AChE, a limited reactivation capacity for BChE was expected. However, 37 oximes reactivated tabun-inhibited BChE more efficiently than the standard antidote 2PAM, and five reached maximal reactivation of 70 %. In addition, toxicity and antidotal studies with lead reactivators in mice showed significantly improved protective indexes compared to 2PAM. Therefore, our findings offer a platform for further development of more potent congenic antidotes in tabun exposure.

antidotes; butyrylcholinesterase; CNS; mutants; nerve agents; organophosphorus compounds; reactivation

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