Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: Application to the reactivation of phosphorylated acetylcholinesterase

摘要

A series of new α-nucleophiles including oximes and amidoximes have been synthesized, and their ability to efficiently and selectively cleave the P-S bond of organophosphorus nerve agents has been evaluated. The relationship between the chemical structure of the α-nucleophiles and their reactivity towards PhX hydrolysis is reported. A significant effect induced by an ortho-hydroxyl group of aryl- and pyridyl-oximes, amidoximes on their organo-phosphono-thioase reactivity was discovered. The evaluation of the initial rates of PhX hydrolysis reaction in the presence of α-nucleophiles allowed the discovery of new uncharged molecules with increased reactivity compared to positively charged 2-pralidoxime used as antidote. The mechanism of their action was studied in details by kinetic analysis, HPLC and LC-MS methods. The most promising structures were then considered as potent in vitro reactivators of phosphylated acetylcholinesterase (AChE), which was confirmed by the preliminary results of AChE reactivation initially inhibited by VX.