Uncharged bis-oximes for accelerated reactivation of organophosphorus- conjugated human acetylcholinesterase

The world community is presently witnessing an unfortunate insidious use of nerve agent organophosphates (OPs) as chemical weapons. Highly efficient antidotes to protect population against those anti acetylcholinesterase (AChE) poisons are not available. The concept of nucleophilic reactivation of OP- inhibited AChE emerged already in 1950s from the monumental studies of Irwin Wilson and colleagues who showed that hydroxamates, oximes and hydroxylamines could reactivate alkylphosphate-inhibited AChE. Subsequent studies over the past five decades, however, have yielded only minor improvements in reactivation rates and a moderately enhanced efficacy for the antidotes. Given the rapid AChE inhibition by nerve agent and pesticide OPs and far slower nucleophilic reactivation by oximes, challenges and

opportunities remain. We proposed to investigate limitations for the oxime reactivation to design accelerated reactivators devoid of those limitations.