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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Oximes in organophosphate poisoning: 60 years of hope and despair
Franz Worek1, Horst Thiermann1, Timo Wille1
1Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Abstract:
The high number of annual fatalities following suicidal poisoning by organophosphorus (OP) pesticides and the recent homicidal use of the chemical warfare nerve agent sarin against civilian population in Syria underlines the continuous threat by these highly toxic agents. The need for an effective treatment of OP poisoning resulted in the implementation of a combination therapy with the muscarinic receptor antagonist atropine and an oxime for the reactivation of OP-inhibited acetylcholinesterase (AChE). Since the invention of the first clinically used oxime pralidoxime (2-PAM) in the 1950s ongoing research attempted to identify more effective oximes. In fact, several thousand oximes were synthesized in the past six decades. These include charged and non-charged compounds, mono- and bispyridinium oximes, asymmetric oximes, oximes with different substitutes and more recently non-oxime reactivators. Multiple in vitro and in vivo studies investigated the potential of oximes to reactivate OP-inhibited AChE and to reverse OP-induced cholinergic signs. Depending on the experimental model, the investigated species and the tested OP largely variable results were obtained by different laboratories. These findings and the inconsistent effectiveness of oximes in the treatment of OP-pesticide poisoned patients led to a continuous discussion on the value of oximes. In order to provide a forward-looking evaluation of the significance of oximes in OP poisoning multiple aspects, including intrinsic toxicity, in vitro reactivation potency, efficacy and pharmacokinetics, as well as the impact of the causative OP have to be considered. The different influencing factors in order to define the benefit and limitations of oximes in OP poisoning will be discussed.
Insights
Organophosphorus poisoning remains a significant threat. While oximes are used to reactivate inhibited acetylcholinesterase, their effectiveness varies, necessitating a comprehensive evaluation of their benefits and limitations.
Area of Science:
- Toxicology
- Pharmacology
- Medicinal Chemistry
Background:
- Organophosphorus (OP) compounds, including pesticides and nerve agents like sarin, pose a continuous global health threat due to high poisoning fatalities.
- Current treatment for OP poisoning involves a combination therapy of atropine and oximes to reactivate inhibited acetylcholinesterase (AChE).
- Despite decades of research and synthesis of thousands of oximes, their clinical effectiveness in treating OP poisoning remains inconsistent, sparking ongoing debate.
Purpose of the Study:
- To critically evaluate the significance of oximes in treating organophosphorus poisoning.
- To provide a forward-looking assessment of oxime efficacy by considering multiple influencing factors.
- To define the benefits and limitations of oximes in the context of OP poisoning.
Main Methods:
- Review of in vitro and in vivo studies investigating oxime potential to reactivate OP-inhibited AChE.
- Analysis of factors influencing oxime effectiveness, including intrinsic toxicity, reactivation potency, pharmacokinetics, and the specific OP agent.
- Discussion of variable results obtained across different experimental models, species, and OP compounds.
Main Results:
- Numerous oximes, including charged, non-charged, mono-, and bispyridinium variants, have been developed over six decades.
- In vitro and in vivo studies show largely variable results regarding oxime efficacy in reactivating AChE and reversing OP toxicity.
- Inconsistent effectiveness of oximes in clinical settings contributes to the ongoing discussion about their therapeutic value.
Conclusions:
- A comprehensive evaluation of oximes requires consideration of intrinsic toxicity, in vitro reactivation, in vivo efficacy, pharmacokinetics, and the nature of the OP agent.
- The variability in research findings and clinical outcomes highlights the complex nature of OP poisoning treatment.
- Further research is needed to fully elucidate the benefits and limitations of different oximes for specific OP poisoning scenarios.
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