Imidazole Aldoximes Effective in Assisting Butyrylcholinesterase Catalysis of Organophosphate Detoxification

Abstract

Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP–hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP–hBChE conjugate.

Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6

“…Current research is directed to develop primarily new BChE-specific reactivators to turn plasma BChE into a pseudocatalytic scavenger or to even augment this process by administration of recombinant BChE (Kovarik et al 2010;Radić et al 2013;Elsinghorst et al 2013;Nachon et al 2013;Sit et al 2014). As a short-term solution, administration of the licensed obidoxime or HI-6 as oxime in advanced development together with additionalby itself stoichiometric-AChE and/or BChE from blood products is a practical approach to elevate the oximemediated pseudocatalytic breakdown of VX in the vascular compartment to decrease the toxic body load and improve physical recovery.…”

“…By now the reactivation of nerve agent-inhibited BChE using the approved (bis-)pyridinium oximes obidoxime or pralidoxime is rather weak (Aurbek et al 2009;Elsinghorst et al 2013). Current research is directed toward synthesizing oximes with new scaffolds combining high affinity and reactivatability toward BChE in plasma to generate an effective pseudocatalytic scavenger (Kovarik et al 2010;Radić et al 2013;Sit et al 2014). …”

Synthesis and in vitro kinetic evaluation of N-thiazolylacetamido monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE)

“…18 Over past few decades, numerous structurally divergent oxime reactivators were synthesized and evaluated for their efficacies against acute OP poisoning. [19][20][21][22][23][24][25][26][27] As newly synthesized compounds cannot be evaluated on humans for ethical reasons hence studies on animals and human enzymes are the mainstay for understanding the pharmacological and toxicological interactions between the antidotes and the OP-enzyme complexes. [28][29][30] In the development of versatile and effective medical countermeasures against acute OP poisoning, extensive variations in the structural features of oxime reactivators are needed for further refinement to shape-up a broad spectrum antidote.…”

Development of quantitative structure activity relationships for the binding affinity of methoxypyridinium cations for human acetylcholinesterase

“…Among the most successful of the oximes is 2-pralidoxime (2-PAM), which is one of the treatments of choice for victims of OP intoxication. 5 Despite the success of 2-PAM and similar oximes in treating OP intoxication they remain a therapy limited to the peripheral nervous system, as it does not cross the blood brain barrier (BBB). Thus, there has been work toward the development of treatments of OP intoxication that are more efficacious and will cross the BBB.…”