title: Syntheses and in vitro evaluations of uncharged reactivators for human acetylcholinesterase inhibited by organophosphorus nerve agents.
abstract: Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant K(D) of inhibited enzyme-oxime complex, the reactivity rate constant kr and the second order reactivation rate constant k(r2) have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun-inhibited hAChE equivalent to those of 2-PAM.
authors.affiliation: COBRA - CNRS UMR 6014 & FR 3038, Rue Lucien Tesnière, 76821 Mont Saint Aignan, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Renou
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mercey
authors.forename: Tristan
authors.initials: T
authors.lastname: Verdelet
authors.forename: Emilia
authors.initials: E
authors.lastname: Păunescu
authors.forename: Emilie
authors.initials: E
authors.lastname: Gillon
authors.forename: Mélanie
authors.initials: M
authors.lastname: Arboléas
authors.forename: Mélanie
authors.initials: M
authors.lastname: Loiodice
authors.forename: Maria
authors.initials: M
authors.lastname: Kliachyna
authors.forename: Rachid
authors.initials: R
authors.lastname: Baati
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jean
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004563:Electrochemistry; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009768:Obidoxime Chloride / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D058851:GPI-Linked Proteins; D009943:Organophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D011994:Recombinant Proteins; D009768:Obidoxime Chloride; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime