engleski

Evaluation of bisquaternary oximes potency in reactivation of tabun-phosphorylated acetylcholinesterase

The mechanism of nerve agent tabun poisoning involves phosphorylation of a serine hydroxyl group in the active site of human acetylcholinesterase (AChE ; EC 3.1.1.7), leading to inactivation of this essential enzyme. One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with a site-directed nucleophile such as an oxime. We evaluated the ability of eleven bisquaternary oximes to reactivate tabun-inhibited human erythrocyte AChE. Oxime structures varied in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring. Since oximes are also reversible inhibitors of AChE, we measured reversible inhibition of native AChE by these oximes and determined their protective effect against AChE inactivation by tabun as well. Using molecular mechanics we investigated structural features of the oximes and performed conformational analysis to determine the flexibility of the oxime molecules. Tabun-inhibited AChE was completely reactivated by bispyridinium oximes with oxime group on the para position. The most potent reactivators have linker with three or four CH2 groups. Semi-empirical calculations showed that differences in rates probably do not origin from different electron density on the oxygen of the oxime group, but can be explained by the steric hindrance of the oxime group within the molecule. Although oximes with oxime group in ortho position or with imidazolium ring did not show significant reactivation ability, these oximes might be of interest as a pretreatment drug due to their high affinity for the native AChE.

antidote; acetylcholinesterase; nerve warfare agent; organophosphorus compounds; oximes

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