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.

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

“…IR (cm À1 ): 3291 (amine N-H), 3119 (aromatic C-H), 1628-1505 (C ¼ N and C ¼ C), 1293 and 1247 (C-N), 780 (C-H out of plane (Di-1,2) General procedure for guanylhydrazones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) Aminoguanidine hydrochloride (1.4 mmol) dissolved in 20 mL of 95% ethanol, the corresponding aldehyde (1 mmol) and two drops of HCl (0.6 M) were added to a 50.0 mL round-bottom flask. The solution was stirred and heated under reflux.…”

“…To reactivate inhibited and phosphorylated AChE, it is necessary to use agents with the appropriate capacity to execute a nucleophilic attack on the phosphorus atom bound to Ser203, leading to the reactivation of the function of this serine. The AChE reactivator agents are mainly cationic oximes 7 , which are effective but, unfortunately, not appropriate against all neurotoxic organophosphorus agents 8 , thereby necessitating the development of new and more effective agents for the protection of all humanity.…”

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

“…Specifically, obidoxime should be the first choice compound in combination with atropine and diazepam for a positive clinical outcome (Stojiljkovic 2006). Since the first use of pralidoxime against OPP intoxication, over 300 different oximes have been synthesized and evaluated (Musilek 2011a). From these, there are some very promising novel reactivators produced in the last decade.…”

“…However, these reactivators were primarily aimed to diminish the intoxications by highly toxic nerve agents (Musilek 2011a). Thus, their use against OPP intoxications was usually made as a side process in the development of nerve agent antidotes.…”

“…There were many attempts to develop potent AChE reactivators for treatment of OPP poisoning (Musilek 2011a). Besides the oximes developed against nerve agents (Musilek 2007b), there were over 300 oximes prepared and tested.…”