A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers

Katalinić, Maja; Hrvat, Nikolina Maček; Baumann, Krešimir; Piperčić, Sara Morasi; Makarić, Sandro; Tomić, Srđanka; Jović, Ozren; Hrenar, Tomica; Miličević, Ante; Jelić, Dubravko; Žunec, Suzana; Primožič, Ines; Kovarik, Zrinka

doi:10.1016/j.taap.2016.09.015

Cited by 43 publications

(35 citation statements)

References 52 publications

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“…Hence, an enzyme–reactivator combination, catalytic to the organophosphate hydrolysis, rather than stoichiometric to conjugation, would greatly reduce doses needed for scavenging. The degradation of OPs in whole human blood observed with both oximes 16 and 18 represents a significant improvement compared with some of our previous ex vivo studies, in which any significant scavenging effect was observed only when the blood was supplemented with suitable hAChE mutants or hBChE. Owing to the financial costs of generating such exogenous enzymes, their short circulation time, and the immunity challenges that arise, the design of oximes with an ability to reactivate native AChE and/or BChE effectively provides a much more desirable approach.…”

Section: Discussionmentioning

confidence: 86%

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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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Section: Discussionmentioning

confidence: 86%

“…), the maximal reactivation (React max ) and the time to maximal reactivation ( t ) were evaluated from at least three experiments at 25 °C. [b] From Katalinić et al . [c] The observed first‐order reactivation rate constant ( k obs ±S.D.…”

Section: Resultsmentioning

confidence: 99%

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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“…Reactivation of the enzyme was measured immediately upon addition of ATCh at nine time points until reaching maximal percentage of reactivation (React max ). Reactivation screening was conducted at a given oxime concentration (0.1 or 1 m m ) up to 24 h, wherefrom the observed first‐order reactivation rate constant ( k obs ) and maximal percentage of reactivation (React max ) were determined as previously described . More detailed reactivation kinetics using a wider oxime concentration range enables the determination of reactivation constants: k 2 (maximal first‐order reactivation rate constant), K ox (apparent phosphylated enzyme‐oxime dissociation constant) and k r (second‐order reactivation rate constant) as described previously …”

Section: Methodsmentioning

confidence: 99%

Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase

Kovarik

Kalisiak

Hrvat

et al. 2019

Chemistry A European J

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Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post‐exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks. We identified several oximes with significantly improved in vitro reactivating potential for tabun‐inhibited human AChE, and in vivo antidotal efficacies in tabun‐exposed mice. Our findings offer a significantly improved platform for further development of antidotes and scavengers directed against tabun and related phosphoramidate exposures, such as the Novichok compounds.

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“…A nanomolar activity was found for N-propylphthalimideand 4-vinylbenzyl-substituted benzimidazole salts (compounds d and e, Figure 1) [11]. A large group of imidazolium and benzimidazolium oximes was designed for reactivation of phosphylated human BuChE [12]. A prominent (nanomolar) activity against AChE/BuChE was found for the pyrazolobenzothiazine-benzimidazole hybrids (compound f, Figure 1) [13] and the benzimidazole-based organophosphorus compounds [14].…”

Section: Introductionmentioning

confidence: 99%

Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

et al. 2019

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In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined.The modified Ellman's spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC 50 80-90 nM) AChE and moderate (IC 50 5-0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure-activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

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A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers

Cited by 43 publications

References 52 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

Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase

Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

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