title: A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers.
abstract: A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC 3.1.1.8) as a stoichiometric bioscavenger efficient in preventing cholinergic crises caused by acetylcholinesterase (AChE, EC 3.1.1.7) inhibition. An additional improvement in medical countermeasures would be to use oximes that could reactivate BChE as well to upgrade bioscavenging from stoichiometric to oxime-assisted catalytic. Therefore, in this paper we investigated the potency of 39 imidazolium and benzimidazolium oximes (36 compounds synthesized for the first time) to be considered as the reactivators specifically designed for reactivation of phosphylated human BChE. Their efficiency in the reactivation of paraoxon-, VX-, and tabun-inhibited human BChE, as well as human AChE was tested and compared with the efficiencies of HI-6 and obidoxime, used in medical practice today. A comprehensive analysis was performed for the most promising oximes defining kinetic parameters of reactivation as well as interactions with uninhibited BChE. Furthermore, experimental data were compared with computational studies (docking, QSAR analysis) as a starting point in future oxime structure refinement. Considering the strict criteria set for in vivo applications, we determined the cytotoxicity of lead oximes on two cell lines. Among the tested oxime library, one imidazolium compound was selected for preliminary in vivo antidotal study in mice. The obtained protection in VX poisoning outlines its potential in development oxime-assisted OP-bioscavenging with BChE.
authors.affiliation: Institute for Medical Research and Occupational Health, POB 291, HR-10001 Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Katalinić
authors.affiliation: Institute for Medical Research and Occupational Health, POB 291, HR-10001 Zagreb, Croatia.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Maček Hrvat
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia.
authors.forename: Krešimir
authors.initials: K
authors.lastname: Baumann
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia.
authors.forename: Sara
authors.initials: S
authors.lastname: Morasi Piperčić
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia.
authors.forename: Sandro
authors.initials: S
authors.lastname: Makarić
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia.
authors.forename: Srđanka
authors.initials: S
authors.lastname: Tomić
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia.
authors.forename: Ozren
authors.initials: O
authors.lastname: Jović
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia.
authors.forename: Tomica
authors.initials: T
authors.lastname: Hrenar
authors.affiliation: Institute for Medical Research and Occupational Health, POB 291, HR-10001 Zagreb, Croatia.
authors.forename: Ante
authors.initials: A
authors.lastname: Miličević
authors.affiliation: Fidelta Ltd., HR-10001 Zagreb, Croatia.
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.affiliation: Institute for Medical Research and Occupational Health, POB 291, HR-10001 Zagreb, Croatia.
authors.forename: Suzana
authors.initials: S
authors.lastname: Žunec
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia. Electronic address: ines.primozic@chem.pmf.hr.
authors.forename: Ines
authors.initials: I
authors.lastname: Primožič
authors.affiliation: Institute for Medical Research and Occupational Health, POB 291, HR-10001 Zagreb, Croatia. Electronic address: zkovarik@imi.hr.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D000067397:Nerve Agents / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology*
chemical_list: D000067397:Nerve Agents; D010091:Oximes; D002091:Butyrylcholinesterase
keywords: Antidotes; Benzimidazole oximes; Butyrylcholinesterase; Imidazole oximes; Nerve agents; Reactivation