Synthesis of the novel series of bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase

doi:10.1016/j.bmcl.2005.10.059

Bioorganic & Medicinal Chemistry Letters

Volume 16, Issue 3, 1 February 2006, Pages 622-627

https://doi.org/10.1016/j.bmcl.2005.10.059 Get rights and content

Abstract

Six potential AChE reactivators were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by insecticide chlorpyrifos was tested in vitro. According to the results, (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as constitution of the linking chain between both pyridinium rings, position of the oxime moiety at the pyridinium ring and presence of quaternary nitrogens.

Graphical abstract

A series of novel bisquaternary reactivators of acetylcholinesterase (AChE) with (E)-but-2-ene connecting chain was synthesized and evaluated on chlorpyrifos-inhibited AChE with promising results.

Section snippets

Acknowledgments

The authors express their appreciation to Mrs. M. Hrabinova for her technical assistance. The work was supported by the grant of Grant Agency of Charles University No. 302/2005/B-CH/FaF and by the grant of Ministry of Defence of Czech Republic No. ONVLAJEP20031.

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Comparison of the reactivation rates of acetylcholinesterase modified by structurally different organophosphates using novel pyridinium oximes
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Herein, a series of new oxime structures were examined for their ability to reactivate the three different OP-AChE conjugates and certain trends were uncovered worthy of note. Oximes with aliphatic side chains mostly showed concentration-dependent reactivation of EEAChE while compounds with heterocyclic linkers showed better reactivation at lower concentrations (10−4 M and 10-5 M) compared with higher concentration (10-3 M) (Musilek et al., 2007a, 2006). Analogs bearing the oxime in the 2- and 4-position were better reactivators than those with oximes in the 3-position.
A novel panel of oximes were synthesized, which have displayed varying degree of reactivation ability towards different organophosphorus (OP) modified cholinesterases. In the present article, we report a comparative reactivation profile of a series of quaternary pyridinium-oximes for electric eel acetylcholinesterase (EEAChE) inhibited by the organophosphorus (OP) inhibitors methyl paraoxon (MePOX), ethyl paraoxon (POX; paraoxon) and diisopropyl fluorophosphate (DFP) that are distinguishable as dimethoxyphosphoryl, diethoxyphosphoryl and diisopropoxyphosphoryl AChE-OP-adducts. Most of the 59-oximes tested led to faster and more extensive reactivation of MePOX- and POX-inhibited EEAChE as compared to DFP-modified EEAChE. All were effective reactivators of three OP-modified EEAChE conjugates showing 18–21% reactivation for DFP-inhibited AChE and ≥45% reactivation for MePOX- and POX-inhibited EEAChE. Oximes 7 and 8 showed k_r values better than pralidoxime (1) for DFP-inhibited EEAChE. Reactivation rates determined at different inhibition times showed no significant change in k_r values during 0–90 min incubation with three OPs. However, a 34–72% decrease in k_r for MePOX and POX and > 95% decrease in k_r for DFP-inhibited EEAChE was observed after 24 h of OP-exposure (aging).
Synthesis and in vitro evaluation of neutral aryloximes as reactivators of Electrophorus eel acetylcholinesterase inhibited by NEMP, a VX surrogate
2019, Chemico-Biological Interactions
Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.
Investigation of the reactivation kinetics of a large series of bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase
2016, Toxicology Letters
The limited effectiveness of the established oximes obidoxime and pralidoxime resulted in ongoing research on novel oximes for the reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OP). In order to get more insight into the ability of bispyridinium oximes to reactivate human AChE inhibited by structurally different OP the reactivation kinetics of 31 compounds was determined with tabun-, cyclosarin- and paraoxon-inhibited AChE under identical experimental conditions. The determined affinity (K_D), reactivity (k_r) and hybrid reactivation rate constants (k_r2) enabled theoretical calculations and gave insight into distinct structural features which are important for the reactivation of AChE inhibited by different OP. Several oximes with superior reactivating potency towards selective OP–AChE conjugates were identified but none of the tested oximes can be considered as a broad spectrum reactivator. In the end, the data of this and previous studies gives rise to the question whether further modifications of the bispyridinium structure could ever result in a universal reactivator or whether future research should be directed to different templates.
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2015, Handbook of Toxicology of Chemical Warfare Agents: Second Edition
In this chapter, recent knowledge regarding development of cholinesterase reactivators is discussed. The major objective is to demonstrate various approaches involved in synthesis and preparation of new candidates for reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus nerve agents or pesticides; describe several structural factors necessary for satisfactory reactivation; introduce currently promising oximes; and set forth novel trends in development of novel AChE reactivators.
Zn<sup>II</sup>/pyridyloxime complexes as potential reactivators of OP-inhibited acetylcholinesterase: In vitro and docking simulation studies
2014, Journal of Inorganic Biochemistry
In order to investigate the ability of metal complexes to act as reactivators of organophosphorus compounds (OP)-inhibited acetylcholinesterase (AChE), we have synthesized and crystallographically characterized three novel mononuclear Zn^II complexes formulated as [ZnCl₂{(4-py)CHNOH}₂] (1), [ZnBr₂{(4-py)CHNOH}₂] (2) and [Zn(O₂CMe)₂{(4-py)CHNOH}₂]∙2MeCN (3∙ 2MeCN), where (4-py)CHNOH is 4-pyridinealdoxime. Their reactivation potency was tested in vitro with a slight modification of the Ellman's method using Electric eel acetylcholinesterase and the insecticide paraoxon (diethyl 4-nitrophenyl phosphate) as inhibitor. The activity of the already reported complex [Zn₂(O₂CPh)₂{(4-py)CHNOH}₂]·2MeCN (4·2MeCN) and of the clinically used drug obidoxime 1,1′-[oxybis(methylene)]bis{4-[(E)- (hydroxyimino)methyl]pyridinium} was also examined. The results of the in vitro experiments demonstrate moderate reactivation of the metal complexes compared to the drug obidoxime. On the other hand, it is clearly shown that the metal complex is the responsible molecular entity for the observed activity, as the reactivation efficacy of the organic ligand (4-pyridinealdoxime) is found to be inconsequential. Docking simulation studies were performed in the light of predicted complex-enzyme interactions using the paraoxon-inhibited enzyme along with the four Zn^II complexes and obidoxime as a reference reactivator. The results showed that the three mononuclear metal complexes possess the required characteristics to be accommodated into the active site of AChE, while the entrance of the dinuclear Zn^II compound is unsuccessful. An interesting outcome of docking simulations is the fact that the mononuclear compounds accommodate into the active site of AChE in a similar mode as obidoxime.

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Synthesis of the novel series of bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase

Abstract

Graphical abstract

Section snippets

Acknowledgments

Pharmacol. Ther.

Tetrahedron Lett.

Toxicology

Toxicology

J. Emerg. Med.

FEBS Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Chem. Biol.

J. Toxicol., Clin. Toxicol.

J. Appl. Biomed.

J. Pharmacol. Exp. Ther.