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Synthesis and in vitro screening of N-phenacylpyridinium oximes as reactivators of organophosphorus (OP)-inhibited electric eel acetylcholinesterase (AChE)

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Abstract

Pyridinium oxime-based drugs are generally used in the treatment of acute organophosphorus (OP) nerve agent poisoning. In this regard, a series of mono-pyridinium oximes bearing substituted phenacyl moieties as side chain were synthesized and screened for their in vitro reactivation efficacies against electric eel acetylcholinesterase (AChE) inhibited by OP inhibitors such as DFP, sarin and VX. The results of the in vitro reactivation data of the synthesized compounds were compared to standard antidotes 2-PAM and obidoxime. Among the synthesized compounds, 1a, 2a, 7a, 8a, 11a, 12a, 13a, 14a and 16a have shown better reactivation efficacy than 2-PAM and obidoxime against VX-inhibited AChE. Oximes 8a, 8b, 11a and 12a were at par with obidoxime in the reactivation of sarin-inhibited AChE. The pKa values for all the oximes were determined and correlated with their observed reactivation potential.

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Abbreviations

AChE:

Acetylcholinesterase

2-PAM:

2-(hydroxyiminomethyl)-1-methylpyridinium chloride

DFP:

Diisopropylfluorophosphate

VX:

O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate

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Acknowledgments

Authors acknowledge Director, Defence R&D Establishment, Gwalior, for his keen interest throughout the research work. AKV is thankful to Defence Research and Development Organization (DRDO), New Delhi, for financial support. Authors are also thankful to Dr. D. K. Dubey for his helpful suggestions. Authors also extend their gratitude to Mr. A. K. Shrivastava for spectral characterization as well as elemental analysis.

Conflict of interest

Authors declared no conflict of interest.

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Authors and Affiliations

  1. Process Technology Development Division, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, India

    Aditya Kapil Valiveti, Jyotiranjan Acharya, Ajay Pratap & Mahabir Parshad Kaushik

  2. School of Studies in Chemistry, Jiwaji University, Gwalior, India

    Anand K. Halve

Authors
  1. Aditya Kapil Valiveti
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  2. Jyotiranjan Acharya
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  3. Ajay Pratap
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  4. Anand K. Halve
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  5. Mahabir Parshad Kaushik
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Correspondence to Jyotiranjan Acharya.

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Valiveti, A.K., Acharya, J., Pratap, A. et al. Synthesis and in vitro screening of N-phenacylpyridinium oximes as reactivators of organophosphorus (OP)-inhibited electric eel acetylcholinesterase (AChE). Med Chem Res 24, 3353–3371 (2015). https://doi.org/10.1007/s00044-015-1384-y

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