A new group of monoquaternary reactivators of acetylcholinesterase inhibited by nerve agents.
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.
Picha
Jan
J
Department of Organic Chemistry, Prague Institute of Chemical Technology, Technicka 5, Prague 16628, Czech Republic.
Kuca
Kamil
K
Kivala
Milan
M
Kohout
Michal
M
Cabal
Jiri
J
Liska
Frantisek
F
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
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