title: Monoquaternary pyridinium salts with modified side chain-synthesis and evaluation on model of tabun- and paraoxon-inhibited acetylcholinesterase.
abstract: Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.
authors.affiliation: Department of Toxicology, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. musilek@pmfhk.cz
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Jiri
authors.initials: J
authors.lastname: Kucera
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Dohnal
authors.forename: Veronika
authors.initials: V
authors.lastname: Opletalova
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D015394:Molecular Structure; D010755:Organophosphates / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010261:Paraoxon / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D020536:Enzyme Activators; D010755:Organophosphates; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; D010261:Paraoxon; C009374:tabun