New group of xylene linker-containing acetylcholinesterase reactivators as antidotes against the nerve agent cyclosarin

Abstract

Nerve agents such as sarin, cyclosarin and tabun are organophosphorus substances able to inhibit the enzyme acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None of the known AChE reactivators is able to reactivate AChE inhibited by all nerve agents used. In this work, reactivation potency of nine newly developed AChE reactivators with an incorporated xylene ring in their structure was measured in vitro. Cyclosarin was chosen as an appropriate member of the nerve agent family. Reactivation potency of the tested AChE reactivators was compared with the gold standard of AChE reactivators--pralidoxime. Two oximes (K107 and K108) surpassed the reactivation potency of pralidoxime. Moreover, from the obtained results it could be deduced that AChE reactivators with a functional oxime group in position-2 are the most potent AChE reactivators in the case of cyclosarin intoxications.

Potency of new structurally different oximes to reactivate cyclosarin-inhibited human brain acetylcholinesterases

“…Our results also confirmed the general understanding that AChE reactivators with the oxime group in the 2-position are the best reactivators of cyclosarininhibited AChE [4,22,23]. Oxime K027 is also in this case an exception, since its oxime group is placed in the 4-position of the pyridinium ring.…”

A comparison of reactivating efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in cyclosarin-and tabun-poisoned rats

“…Unfortunately, the other above mentioned structural features, especially the position of the oxime group in the pyridinium ring, depend on the chemical structure of the AChE reactivators. While the potency of reactivators to reactivate tabun-inhibited AChE with the oxime group in position-4 is higher compared to reactivators with the oxime group at other different positions [11,19,21], AChE reactivators with the oxime group in position-2 are the best reactivators of cyclosarin-inhibited AChE [22,23,24]. On the other hand, the number of aldoxime groups is not so important.…”

Eight new bispyridinium oximes in comparison with the conventional oximes pralidoxime and obidoxime: in vivo efficacy to protect from diisopropylfluorophosphate toxicity

“…K-74 and K-75 were shown to be effective in reactivating AChE inhibited by tabun in vitro (Kuça et al, 2005. Most recently, a group of Koximes containing a xylene linker has been synthesized (Hrabinova et al, 2006;Musilek et al, 2007b). These bisquaternary symmetric pyridinium aldoximes ( Fig.…”

“…These bisquaternary symmetric pyridinium aldoximes ( Fig. 1) with the functional aldoxime group at position 2 (K-107, K-108) or 4 (K-113, K-114) are good in vitro reactivators of tabun-, cyclosarin-and paraoxon-inhibited AChE (Hrabinova et al, 2006;Musilek et al, 2007b).…”