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Archives of Toxicology

, Volume 90, Issue 12, pp 2831–2859 | Cite as

SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides

  • Lukas Gorecki
  • Jan Korabecny
  • Kamil Musilek
  • David Malinak
  • Eugenie Nepovimova
  • Rafael Dolezal
  • Daniel Jun
  • Ondrej Soukup
  • Kamil KucaEmail author
Review Article

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.

Keywords

Acetylcholinesterase Organophosphate Pyridinium oximes Reactivation Nerve agents Uncharged reactivator 

Notes

Acknowledgments

The work was supported by the Long-Term Development of Faculty of Medicine, University of Ostrava, by University of Defence (Long-Term Development Plan—1011), by MH CZ—DRO (University Hospital Hradec Kralove, No. 00179906), by the Czech Science Foundation (No. GA15-16701S) and by specific research (SV/FVZ201601).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Lukas Gorecki
    • 1
    • 2
  • Jan Korabecny
    • 1
    • 2
  • Kamil Musilek
    • 1
    • 2
    • 3
  • David Malinak
    • 1
    • 4
  • Eugenie Nepovimova
    • 1
    • 2
  • Rafael Dolezal
    • 1
    • 3
  • Daniel Jun
    • 1
    • 2
  • Ondrej Soukup
    • 1
    • 2
  • Kamil Kuca
    • 1
    • 3
    Email author
  1. 1.Biomedical Research CentreUniversity Hospital Hradec KraloveHradec KraloveCzech Republic
  2. 2.Department of Toxicology and Military Pharmacy, Faculty of Military Health SciencesUniversity of DefenceHradec KraloveCzech Republic
  3. 3.Department of Chemistry, Faculty of ScienceUniversity of Hradec KraloveHradec KraloveCzech Republic
  4. 4.Department of Physiology and Pathophysiology, Faculty of MedicineUniversity of OstravaOstravaCzech Republic

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