Synthesis and in vitro evaluation of donepezil-based reactivators and analogues for nerve agent-inhibited human acetylcholinesterase

Renou, Julien; Dias, José; Mercey, Guillaume; Verdelet, Tristan; Rousseau, Catherine; Gastellier, Anne-Julie; Arboléas, Mélanie; Touvrey-Loiodice, Mélanie; Baati, Rachid; Jean, Ludovic; Nachon, Florian; Renard, Pierre

doi:10.1039/c5ra25477a

Cited by 32 publications

(23 citation statements)

References 32 publications

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“…With such a low barrier, it appears that AChE reactivation by oximes is solely dependent on the protonation state in the active site rather than nucleophilicity of the oxime. Obviously, binding of the oxime is also important, but this has been largely addressed by experimental and docking studies …”

Section: Discussionmentioning

confidence: 99%

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Driant

Nachon²,

Ollivier

et al. 2017

ChemBioChem

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Acetylcholinesterase (AChE) is an enzyme of the serine hydrolase superfamily and a mediator of the signal transmission at cholinergic synapses catalysing acetylcholine cleavage into an acetate and a choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds. The covalent inhibition of AChE does not revert spontaneously and in order to restore catalytic activity known reactivator compounds have limited action. Simulations of VX-inhibited AChE reactivation by pralidoxime, a classical reactivator, were performed by QM/MM. These simulations allowed for a broader view of the effect of protonation states of active site residues. These calculations provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM was also explored in both protonation states of Glu202, showing that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Since the active site of serine hydrolases is highly conserved, this work shades new insights on the interplay between the triad residues of the catalytic center and this glutamate newly identified as protonatable.

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Section: Discussionmentioning

confidence: 99%

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Driant

Nachon²,

Ollivier

et al. 2017

ChemBioChem

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“…Also, the late stage Sonogashira cross‐coupling of alkyne 1v with 2 , provided the expected 6‐alkynyl‐3‐fluoro‐2‐pyridinaldoxime 3v in excellent yield (87 %), which is an analog of a recently published hybrid reactivator of OP‐inhibited AChE. [14b]…”

Section: Resultsmentioning

confidence: 99%

Sonogashira Reaction of Bromofluoropyridinaldoxime Nuclei: Convergent Synthesis of Functionalized 2‐ and 3‐Fluoropyridine Scaffolds

Yerri

Baati

2018

Eur J Org Chem

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A chemoselective palladium catalyzed Sonogashira cross‐coupling of bromofluoropyridinaldoxime with highly functionalized alkynes is presented. This reaction is fully compatible with unprotected sensitive aldoxime and affords representative underexplored new scaffolds. The process exhibits a broad scope of alkynes, dialkynes, and large functional group compatibility, including the use of non‐radioactive isotopic reporter such as 15N labeled oxime and chiral substrates.

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“…Novelo xime structures based on the Alzheimer's disease drug donepezilbyR enard and co-workers. [109] Chem. Eur.J.…”

Section: Developing Non-permanently Charged Oxime Reactivators Of Op-mentioning

confidence: 99%

“…Renard and co-workers synthesized and tested uncharged oxime reactivators making use of the anti-Alzheimer's disease drug donepezil as ap eripheral site ligand. [109] The benzyl moiety of donepezil wasr eplaced with a3 -hydroxypyridinaldoxime as the nucleophilic portion of the molecule (Figure 23). In total, four variants (28-31)w ere synthesized ande valuated for their reactivation ability versus VX-, sarin-, paraoxon-, and tabun-inhibited hAChE.…”

Section: Developing Non-permanently Charged Oxime Reactivators Of Op-mentioning

confidence: 99%

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

Franjesevic

Sillart

Beck

et al. 2019

Chemistry A European J

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Synthesis and in vitro evaluation of donepezil-based reactivators and analogues for nerve agent-inhibited human acetylcholinesterase

Abstract: Donepezil-based reactivators 1–3 show a better ability (8 fold higher) than pralidoxime to reactivate VX-hAChE, and oxime 2 is 5 to 11 fold more efficient than pralidoxime and HI-6 respectively to reactivate of VX-hBChE.

Cited by 32 publications

References 32 publications

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Sonogashira Reaction of Bromofluoropyridinaldoxime Nuclei: Convergent Synthesis of Functionalized 2‐ and 3‐Fluoropyridine Scaffolds

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

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