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

• DOI: 10.1016/j.ejmech.2014.03.044
• Publication Date: 2014-03-20T01:01:27Z
• Authors: Maria Kliachyna; Gianluca Santoni; Valentin Nussbaum; Julien Renou; Benoit Sanson; Jacques-Philippe ...; Mélanie Arboléas; Mélanie Loiodice; Martin Weik; Ludovic Jean; Pierre-Yves Renard; Florian Nachon; Rachid Baati
• Keywords: Models, Molecular; 0301 basic medicine; Pyridines; MESH: Chemical Warfare Agents; MESH: Molecular Structure; MESH: Dose-Response Relationship; 610; MESH: Drug Design; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry; MESH: Dose-Response Relationship, Drug; Structure-Activity Relationship; 03 medical and health sciences; MESH: Structure-Activity Relationship; MESH: Models; Oximes; Humans; Chemical Warfare Agents; MESH: Humans; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]; Dose-Response Relationship, Drug; Molecular Structure; Molecular Biology/Structural Biology [q-bio.BM]; MESH: Pyridines; Molecular; MESH: Acetylcholinesterase; 540; MESH: Oximes; MESH: Amides; Amides; 3. Good health; Drug Design; Acetylcholinesterase; Tacrine; Cholinesterase Inhibitors; Drug; MESH: Cholinesterase Inhibitors; MESH: Models, Molecular; MESH: Tacrine

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.