Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase.
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.
Université de Strasbourg, Faculté de Pharmacie, CNRS/ UMR 7199 BP 24, 74 route du rhin 67401 Illkirch, France.
Maria
M
Kliachyna
Commissariat à l'Energie Atomique, Institut de Biologie Structurale, F-38054 Grenoble; CNRS, UMR5075, F-38027 Grenoble; Université Joseph Fourier, F-38000, Grenoble, France.
Gianluca
G
Santoni
Université de Strasbourg, Faculté de Pharmacie, CNRS/ UMR 7199 BP 24, 74 route du rhin 67401 Illkirch, France.
Valentin
V
Nussbaum
Normandie University, COBRA, UMR 6014 and FR 3038; University of Rouen; INSA of Rouen; CNRS, 1 rue Tesniere 76821 Mont-Saint-Aignan, Cedex, France.
Julien
J
Renou
Commissariat à l'Energie Atomique, Institut de Biologie Structurale, F-38054 Grenoble; CNRS, UMR5075, F-38027 Grenoble; Université Joseph Fourier, F-38000, Grenoble, France.
Benoit
B
Sanson
Commissariat à l'Energie Atomique, Institut de Biologie Structurale, F-38054 Grenoble; CNRS, UMR5075, F-38027 Grenoble; Université Joseph Fourier, F-38000, Grenoble, France.
Jacques-Philippe
JP
Colletier
Département de Toxicologie, Institut de Recherche Biomédicale des Armées BP7391993 Brétigny/s/Orge, France.
Mélanie
M
Arboléas
Département de Toxicologie, Institut de Recherche Biomédicale des Armées BP7391993 Brétigny/s/Orge, France.
Mélanie
M
Loiodice
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.
Martin
M
Weik
Normandie University, COBRA, UMR 6014 and FR 3038; University of Rouen; INSA of Rouen; CNRS, 1 rue Tesniere 76821 Mont-Saint-Aignan, Cedex, France.
Ludovic
L
Jean
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.
Pierre-Yves
PY
Renard
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.
Florian
F
Nachon
Université de Strasbourg, Faculté de Pharmacie, CNRS/ UMR 7199 BP 24, 74 route du rhin 67401 Illkirch, France. Electronic address: rachid.baati@unistra.fr.
Rachid
R
Baati
D000110:Acetylcholinesterase / Q000378:metabolism*; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D010091:Oximes; D011725:Pyridines; D013619:Tacrine; D000110:Acetylcholinesterase; C023728:acetaldehyde oxime; C023666:pyridine
Hybrids; Organophosphorus nerve agents; Oximes; Pyridinaldoximes; Reactivation of acetylcholinesterase; Tacrine