An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice

Calas, André-Guilhem; Dias, José; Rousseau, Catherine; Arboléas, Mélanie; Touvrey-Loiodice, Mélanie; Mercey, Guillaume; Jean, Ludovic; Renard, Pierre; Nachon, Florian

doi:10.1016/j.cbi.2016.03.009

Cited by 21 publications

(23 citation statements)

References 23 publications

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“…Thus, the desired oximes 15 – 18 were obtained in seven steps from 1 or 2 in overall yields of 4–21 %. Regarding the synthesis of oxime 19 , its preparation was reported earlier …”

Section: Resultsmentioning

confidence: 99%

“…[34] All of them,e xcept 19,h ave optimal values of lipophilicity (log P = 0.9-4.6) and molecular weight( 280-400), and optimal numbers of hydrogen-bond donors (2) and hydrogen-bond acceptors (5-7). Molecular flexibility,a sc haracterised by the number of rotatable bonds (6)(7)(8)(9), is favourable in three out of the five oximes.A lso, the pK a value of the most basic group (i.e.,t he R 3 ÀNH + group;c f. Ta ble 4) is in or almost in the recommended range (7.5-10.0) for oximes [16][17][18][19].T he only shortfall for this group of oximes is ah igherp olar surface area (78-87 2 ), except for oxime 15 (69 2 ). By using the algorithm described by Wager andc o-workers, [35] the central nervous system multi-parameter optimisation score was calculated based on the six fundamentalp hysicochemical parameters (log P,l og D,p K a ,H BD, PSA, MW), for whicht he score for CNS candidates should be !…”

Section: In Silico and In Vitro Determination Of Pk A Valuesmentioning

confidence: 93%

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Potent 3‐Hydroxy‐2‐Pyridine Aldoxime Reactivators of Organophosphate‐Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

Zorbaz

Braïki

Maraković

et al. 2018

Chemistry A European J

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A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential.

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“…Thus, the desired oximes 15 – 18 were obtained in seven steps from 1 or 2 in overall yields of 4–21 %. Regarding the synthesis of oxime 19 , its preparation was reported earlier …”

Section: Resultsmentioning

confidence: 99%

Section: In Silico and In Vitro Determination Of Pk A Valuesmentioning

confidence: 93%

Potent 3‐Hydroxy‐2‐Pyridine Aldoxime Reactivators of Organophosphate‐Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

Zorbaz

Braïki

Maraković

et al. 2018

Chemistry A European J

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“…However, investigation of their pharmacological activity in model animals is only at the beginning (Calas et al . ), and initial screening of these new families of reactivors can be advantageously screened on the simplest Zebrafish model for NA reactivation (Schmidt et al . ; Kovalevsky et al .…”

Section: Post‐exposure Treatmentmentioning

confidence: 99%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

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124

105

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Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for postexposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre-and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE.

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“…On the day of experimentation, mice received intraperitoneal (i.p.) injection of oxime at 23.3 µmol/kg, which corresponds to the highest dose of the soluble free base or 100 µmol/kg analogous with our previous studies [15]. At various time-points (0, 2, 5, 10, 15, 30, 60, and 180 min after oxime injection), the saphenous vein was drilled with a needle and approximately 15 µL of blood was collected with a heparinized capillary tube and deposited in a collection tube containing 2 µL of sodium heparin (Choay ® , Sanofi, France).…”

Section: Blood Samplingmentioning

confidence: 71%

“…The PI corresponds to the ratio of LD 50 of the studied OP agent (either VX or paraoxon) combined with oxime treatment on LD 50 of OP alone. LD 50 (VX) was previously established with a value of 15.4 µg/kg [15].…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime

Calas¹,

Hanak²,

Jaffré³

et al. 2020

Biomolecules

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(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood–brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.

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An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice

Cited by 21 publications

References 23 publications

Potent 3‐Hydroxy‐2‐Pyridine Aldoxime Reactivators of Organophosphate‐Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

Potent 3‐Hydroxy‐2‐Pyridine Aldoxime Reactivators of Organophosphate‐Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime

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