Phenyltetrahydroisoquinoline–Pyridinaldoxime Conjugates as Efficient Uncharged Reactivators for the Dephosphylation of Inhibited Human Acetylcholinesterase

Mercey, Guillaume; Renou, Julien; Verdelet, Tristan; Kliachyna, Maria; Baati, Rachid; Gillon, Émilie; Arboléas, Mélanie; Loiodice, Mélanie; Nachon, Florian; Jean, Ludovic; Renard, Pierre

doi:10.1021/jm3015519

Cited by 53 publications

(45 citation statements)

References 33 publications

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“…For conjugate 3, our results are in line with what Mercey et al had reported, but they did not evaluate the reactivation ability against sarin-inhibited hAChE. 24,25 In contrast to those quaternary oximes, 7g, 7h and 3 emerged as more broad-spectrum for sarin-, VX-and tubaninhibited hAChE, while obidoxime and TMB-4 were less efficient for sarin; HI-6 and MMB-4 were much less efficient for tabun poisoning. We also determined the reactivation potency of imidazolium-2-aldoxime (5b), the results demonstrated that most conjugates showed improved reactivation potency, especially in the cases of 7d, 7g and 7h, which justified the concept of dual-site biding strategy.…”

supporting

confidence: 90%

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New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase

Wei¹,

Zhou³

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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confidence: 90%

“…But all these conjugates are pyridyl aldoximes and they are difficult to prepare due to a long synthetic route, moreover, their reactivation potencies against sarin-inhibited hAChE are still unknown. [24][25][26][27] Hence we sought to develop alternatives of the pyridyl aldoximes.…”

mentioning

confidence: 99%

New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase

Wei¹,

Zhou³

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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“…Recently, the ability of neutral reactivator pyridinealdoxime to reactivate OP inhibited enzyme was reported [23]–[27]. This pyridinealdoxime showed a considerable capacity to reactivate VX-, tabun- and ethyl paraoxan inhibited human AChE [27].…”

Section: Resultsmentioning

confidence: 99%

“…Recently, non-ionic reactivators have been synthesized, which can more easily penetrate the BBB and reactivate the inhibited h AChE [23]–[27]. Non-quaternary pyridinealdoxime compounds exhibited a high potency for the reactivation of VX and tabun-inhibited h AChE.…”

Section: Introductionmentioning

confidence: 99%

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In Silico Studies in Probing the Role of Kinetic and Structural Effects of Different Drugs for the Reactivation of Tabun-Inhibited AChE

Chandar

Kesharwani

et al. 2013

PLoS ONE

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We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ∼2.5 kcal/mol, which was ∼5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O…H and N…H hydrogen bonding and C-H…π non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme.

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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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Phenyltetrahydroisoquinoline–Pyridinaldoxime Conjugates as Efficient Uncharged Reactivators for the Dephosphylation of Inhibited Human Acetylcholinesterase

Cited by 53 publications

References 33 publications

New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase

New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase

In Silico Studies in Probing the Role of Kinetic and Structural Effects of Different Drugs for the Reactivation of Tabun-Inhibited AChE

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

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