title: Monooxime-monocarbamoyl Bispyridinium Xylene-Linked Reactivators of Acetylcholinesterase-Synthesis, In vitro and Toxicity Evaluation, and Docking Studies.
abstract: Acetylcholinesterase (AChE) reactivators are crucial antidotes to organophosphate intoxication. A new series of 26 monooxime-monocarbamoyl xylene-linked bispyridinium compounds was prepared and tested in vitro, along with known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime, K107, K108 and K203), on a model of tabun- and paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Although their ability to reactivate tabun-inhibited AChE did not exceed that of the previously known compounds, some newly prepared compounds showed promising reactivation of pesticide-inhibited AChE. The acute toxicity of the novel compounds was also determined. Docking studies using tabun-inhibited AChE were performed for three compounds of interest. The structure-activity relationship (SAR) study confirmed the apparent influence of the xylene linkage and carbamoyl moiety on the reactivation ability and toxicity of the agents.
authors.affiliation: Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, Hradec Kralove, Czech Republic. musilek@pmfhk.cz
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Holas
authors.forename: Jan
authors.initials: J
authors.lastname: Misik
authors.forename: Miroslav
authors.initials: M
authors.lastname: Pohanka
authors.forename: Ladislav
authors.initials: L
authors.lastname: Novotny
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 / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry*; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis* / Q000633:toxicity; D003198:Computer Simulation; D015195:Drug Design; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D051379:Mice; D010091:Oximes / Q000737:chemistry*; D011726:Pyridinium Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014992:Xylenes / Q000737:chemistry*
chemical_list: D002219:Carbamates; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D014992:Xylenes; D000110:Acetylcholinesterase