Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase

Maria Kliachyna; Gianluca Santoni; Valentin Nussbaum; Julien Renou; Benoit Sanson; Jacques-Philippe Colletier; Mélanie Arboléas; Mélanie Loiodice; Martin Weik; Ludovic Jean; Pierre-Yves Renard; Florian Nachon; Rachid Baati

doi:10.1016/j.ejmech.2014.03.044

Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase

Eur J Med Chem. 2014 May 6:78:455-67. doi: 10.1016/j.ejmech.2014.03.044. Epub 2014 Mar 15.

Affiliations

¹ Université de Strasbourg, Faculté de Pharmacie, CNRS/ UMR 7199 BP 24, 74 route du rhin 67401 Illkirch, France.
² Commissariat à l'Energie Atomique, Institut de Biologie Structurale, F-38054 Grenoble; CNRS, UMR5075, F-38027 Grenoble; Université Joseph Fourier, F-38000, Grenoble, France.
³ Normandie University, COBRA, UMR 6014 and FR 3038; University of Rouen; INSA of Rouen; CNRS, 1 rue Tesniere 76821 Mont-Saint-Aignan, Cedex, France.
⁴ Département de Toxicologie, Institut de Recherche Biomédicale des Armées BP7391993 Brétigny/s/Orge, France.
⁵ Commissariat à l'Energie Atomique, Institut de Biologie Structurale, F-38054 Grenoble; CNRS, UMR5075, F-38027 Grenoble; Université Joseph Fourier, F-38000, Grenoble, France. Electronic address: martin.weik@ibs.fr.
⁶ Normandie University, COBRA, UMR 6014 and FR 3038; University of Rouen; INSA of Rouen; CNRS, 1 rue Tesniere 76821 Mont-Saint-Aignan, Cedex, France. Electronic address: pierre-yves.renard@univ-rouen.fr.
⁷ Commissariat à l'Energie Atomique, Institut de Biologie Structurale, F-38054 Grenoble; CNRS, UMR5075, F-38027 Grenoble; Université Joseph Fourier, F-38000, Grenoble, France; Département de Toxicologie, Institut de Recherche Biomédicale des Armées BP7391993 Brétigny/s/Orge, France. Electronic address: florian@nachon.net.
⁸ Université de Strasbourg, Faculté de Pharmacie, CNRS/ UMR 7199 BP 24, 74 route du rhin 67401 Illkirch, France. Electronic address: rachid.baati@unistra.fr.

PMID: 24704618
DOI: 10.1016/j.ejmech.2014.03.044

Abstract

A series of new uncharged functional acetylcholinesterase (AChE) reactivators including heterodimers of tetrahydroacridine with 3-hydroxy-2-pyridine aldoximes and amidoximes has been synthesized. These novel molecules display in vitro reactivation potencies towards VX-, tabun- and paraoxon-inhibited human AChE that are superior to those of the mono- and bis-pyridinium aldoximes currently used against nerve agent and pesticide poisoning. Furthermore, these uncharged compounds exhibit a broader reactivity spectrum compared to currently approved remediation drugs.

Keywords: Hybrids; Organophosphorus nerve agents; Oximes; Pyridinaldoximes; Reactivation of acetylcholinesterase; Tacrine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism*
Amides / chemistry
Amides / pharmacology
Chemical Warfare Agents / chemical synthesis
Chemical Warfare Agents / chemistry
Chemical Warfare Agents / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Oximes / chemistry
Oximes / pharmacology
Pyridines / chemistry
Pyridines / pharmacology
Structure-Activity Relationship
Tacrine / chemistry
Tacrine / pharmacology

Substances

Amides
Chemical Warfare Agents
Cholinesterase Inhibitors
Oximes
Pyridines
Tacrine
Acetylcholinesterase
acetaldehyde oxime
pyridine