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.

Keywords::

• Nerve agent
• cyclosarin
• reactivation
• acetylcholinesterase
• oxime
• inhibition

Acknowledgement

This study was supported by the grant of Ministry of Defense No. ONVLAJEP 20031 and by a grant from the Grant Agency of Charles University No. 302/2005/B-CH/FaF.