title: Monooxime reactivators of acetylcholinesterase with (E)-but-2-ene linker: preparation and reactivation of tabun- and paraoxon-inhibited acetylcholinesterase.
abstract: Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Fifteen new monooxime reactivators of acetylcholinesterase with a (E)-but-2-ene linker were developed in an effort to extend the properties of K-oxime (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). The known reactivators (pralidoxime, HI-6, obidoxime, K075, K203) and the new compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monooxime reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation comparable with known compounds for paraoxon poisoning. However, extensive differences were found by a SAR study for various substitutions on the non-oxime part of the reactivator molecule.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Holas
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Dohnal
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.forename: Veronika
authors.initials: V
authors.lastname: Opletalova
authors.forename: Martin
authors.initials: M
authors.lastname: Dolezal
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D000931:Antidotes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000506:poisoning; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D010755:Organophosphates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010261:Paraoxon / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase; D010261:Paraoxon; C009374:tabun