title: Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides.
abstract: Organophosphate pesticides (OPPs; e.g. chlorpyrifos, diazinon, paraoxon) are a wide and heterogeneous group of organophosphorus compounds. Their biological activity of inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) ranks them as life endangering agents. The necessary treatment after OPP exposure involves the use of parasympatolytics (e.g. atropine), oxime reactivators (e.g. obidoxime), and anticonvulsive drugs (e.g. diazepam). Therefore, the reactivators of AChE are essential compounds in the treatment of OPP intoxications. Commercial AChE reactivators (e.g. pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) were originally developed for other members of the organophosphate family, such as nerve agents (e.g. sarin, soman, tabun, VX). Pralidoxime, HI-6, and methoxime were found to be weak reactivators of OPP-inhibited AChE. Obidoxime and trimedoxime showed satisfactory reactivation against various OPPs with minor toxicity issues. During the last two decades, the treatment of OPP exposure has become more widely discussed because of growing agricultural production, industrialization, and harmful social issues (e.g. suicides). In this review is the summarized design, evaluation, and structure-activity relationship studies of recently produced AChE reactivators. Since pralidoxime, over 300 oximes have been produced or tested against OPP poisoning, and several novel compounds show very promising abilities as comparable (or higher) to commercial oximes. Some of these are highlighted for their further testing of OPP exposure and, additionally, the main structure-activity relationship of AChE reactivators against OPP is discussed.
authors.affiliation: Department of Toxicology, Trebesska, Hradec Kralove, Czech Republic. musilek@pmfhk.cz
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Martin
authors.initials: M
authors.lastname: Dolezal
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002801:Cholinesterase Reactivators / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors*; D010575:Pesticides / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010575:Pesticides; D000110:Acetylcholinesterase