Naslov
A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers

Autori
Katalinić, Maja ; Maček Hrvat, Nikolina ; Baumann, Krešimir ; Morasi Piperčić, Sara ; Makarić, Sandro ; Tomić, Srđanka ; Jović, Ozren ; Hrenar, Tomica ; Miličević, Ante ; Jelić, Dubravko ; Žunec, Suzana ; Primožič, Ines ; Kovarik, Zrinka

Izvornik
Toxicology and applied pharmacology (0041-008X) 310 (2016); 195-204

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Antidotes ; Benzimidazole oximes ; Butyrylcholinesterase ; Imidazole oximes ; Nerve agents ; Reactivation

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA