title: SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides.
abstract: Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors: Lukas
authors: L
authors: Gorecki
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors: Jan
authors: J
authors: Korabecny
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.|Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
authors: Kamil
authors: K
authors: Musilek
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Physiology and Pathophysiology, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00, Ostrava, Czech Republic.
authors: David
authors: D
authors: Malinak
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors: Eugenie
authors: E
authors: Nepovimova
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
authors: Rafael
authors: R
authors: Dolezal
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors: Daniel
authors: D
authors: Jun
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors: Ondrej
authors: O
authors: Soukup
authors: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. kamil.kuca@fnhk.cz.|Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic. kamil.kuca@fnhk.cz.
authors: Kamil
authors: K
authors: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D000067397:Nerve Agents / Q000737:chemistry / Q000633:toxicity; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010575:Pesticides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011487:Protein Conformation; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D008024:Ligands; D000067397:Nerve Agents; D009943:Organophosphorus Compounds; D010575:Pesticides; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Nerve agents; Organophosphate; Pyridinium oximes; Reactivation; Uncharged reactivator