Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

“…IR (cm À1 ): 3291 (amine N-H), 3119 (aromatic C-H), 1628-1505 (C ¼ N and C ¼ C), 1293 and 1247 (C-N), 780 (C-H out of plane (Di-1,2) General procedure for guanylhydrazones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) Aminoguanidine hydrochloride (1.4 mmol) dissolved in 20 mL of 95% ethanol, the corresponding aldehyde (1 mmol) and two drops of HCl (0.6 M) were added to a 50.0 mL round-bottom flask. The solution was stirred and heated under reflux.…”

“…The irreversible inhibitors are basically neurotoxic organophosphorus compounds, normally used as pesticides, insecticides, and chemical warfare agents 3,4 . These agents lead to the phosphorylation of Ser203, which is the most important active amino acid involved in ACh hydrolysis, at the active site of AChE, leading to complete inhibition of this enzyme 5 .…”

The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats

“…Our laboratories have synthesized a series of substituted phenoxyalkyl pyridinium oximes, of which several show efficacy as brain-penetrating reactivators of AChE inhibited by our nerve agent surrogates, NIMP and NEMP (Chambers et al, 2013). Because they are strong nucleophiles, these novel oximes were also previously tested in vitro for PON1 enhancement (Chambers et al, 2015).…”

“…From our previous in vitro study (Chambers et al, 2015), a subset of the most efficacious enhancers was selected for these in vivo tests. The OPs selected as substrates for PON1 were surrogates for the nerve agents sarin and VX that our laboratories have synthesized and used in AChE reactivation studies (Meek et al, 2012;Chambers et al, 2013) and in the in vitro PON1 enhancer studies (Chambers et al, 2015). The goal of the present study was to determine if nucleophiles that can enhance PON1-mediated detoxication of OPs in vitro can provide protection from circulating toxic OPs in an in vivo system, thereby identifying compounds with the potential for being developed into nerve agent therapeutics possessing a novel mechanism of action.…”

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

“…Being quaternary ammonium salts, majority of these oximes are unable to cross the blood brain barrier. 14,15 Further, oxime treatments are ineffective toward the aged enzyme. Moreover, the intrinsic toxicities of these oximes exert deleterious side effects.…”