title: A new group of monoquaternary reactivators of acetylcholinesterase inhibited by nerve agents.
abstract: Reactivators of acetylcholinesterase (AChE; EC 3.1.1.7) are able to treat intoxication by organophosphorus compounds, especially with pesticides or nerve agents. Owing to the fact that there exists no universal "broad-spectrum" reactivator of organophosphates-inhibited AChE, many laboratories have synthesized new AChE reactivators. Here, we synthesized five new and three previously known quaternary monopyridinium oximes as potential reactivators of AChE inhibited by nerve agents. Potencies to cleave p-nitrophenyl acetate (PNPA), which is commonly used as a model substrate of nerve agents, were measured. Their cleaving potencies were compared with 4-PAM (4-hydroxyiminomethyl-1-methylpyridinium iodide), which is derived from the structure of the currently used AChE-reactivator 2-PAM (2-hydroxyiminomethyl-1-methylpyridinium iodide). Three newly synthesized oximes achieved similar nucleophilicity at the similar pKa according to 4-PAM, which is very promising for using these derivatives as AChE reactivators.
authors.affiliation: Department of Organic Chemistry, Prague Institute of Chemical Technology, Technicka 5, Prague 16628, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Picha
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Milan
authors.initials: M
authors.lastname: Kivala
authors.forename: Michal
authors.initials: M
authors.lastname: Kohout
authors.forename: Jiri
authors.initials: J
authors.lastname: Cabal
authors.forename: Frantisek
authors.initials: F
authors.lastname: Liska
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis* / Q000494:pharmacology; D004357:Drug Synergism; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D009596:Nitrophenols / Q000378:metabolism; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000737:chemistry; D011726:Pyridinium Compounds / Q000737:chemistry
chemical_list: C505765:4-hydroxyiminomethyl-1-methylpyridinium iodide; D002801:Cholinesterase Reactivators; D008024:Ligands; D009596:Nitrophenols; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; C008642:4-nitrophenyl acetate; D000110:Acetylcholinesterase; C028797:pralidoxime