Design, Evaluation and Structure---Activity Relationship Studies of theAChE Reactivators Against Organophosphorus Pesticides Kamil Musilek, 1,2 Martin Dolezal, 3 Frank Gunn-Moore, 4 and Kamil Kuca 2,5 1 Department of Toxicology, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic 2 Department of Chemistry, Faculty of Science, University of Jan Evangelista Purkyne, Ceske mladeze 8, 400 96 Usti nad Labem, Czech Republic 3 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 4 School of Biology, University of St. Andrews, Bute Building, St. Andrews KY16 9TS, Fife, United Kingdom 5 Center of Advanced Studies, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic Published online 21 December 2009 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.20192 . Abstract: Organophosphate pesticides (OPPs; e.g. chlorpyrifos, diazinon, paraoxon) are a wide and het- erogeneous group of organophosphorus compounds. Their biological activity of inhibiting acet- ylcholinesterase (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. & 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 4, 548–575, 2011 Key words: acetylcholinesterase; pesticide; insecticide; reactivation; oxime; SAR Contract grant sponsor: Ministry of Education,Youth and Sports (Czech Republic); Contract grant number: ME09086. Correspondence to: Kamil Musilek, Department of Toxicology, Faculty of Military Health Sciences,Trebesska 1575, 500 01 Hradec Kralove, Czech Republic, E-mail: musilek@pmfhk.cz, kamil.musilek@gmail.com Medicinal Research Reviews, 31, No. 4, 548--575, 2011 & 2009 Wiley Periodicals, Inc.