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Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A

  • Daniëlle Copmans
    Daniëlle Copmans
    Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium
  • Mostafa Rateb
    Mostafa Rateb
    Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, United Kingdom
    Faculty of Pharmacy, Pharmacognosy Department, Beni-Suef University, Beni-Suef 62513, Egypt
  • Jioji N. Tabudravu
    Jioji N. Tabudravu
    Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, United Kingdom
  • Mercedes Pérez-Bonilla
    Mercedes Pérez-Bonilla
    Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Parque Tecnológico de Ciencias de la Salud, E-18016 Granada, Spain
  • Nina Dirkx
    Nina Dirkx
    Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium
    More by Nina Dirkx
  • Riccardo Vallorani
    Riccardo Vallorani
    Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium
  • Caridad Diaz
    Caridad Diaz
    Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Parque Tecnológico de Ciencias de la Salud, E-18016 Granada, Spain
    More by Caridad Diaz
  • José Pérez del Palacio
    José Pérez del Palacio
    Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Parque Tecnológico de Ciencias de la Salud, E-18016 Granada, Spain
  • Alan J. Smith
    Alan J. Smith
    Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, United Kingdom
  • Rainer Ebel
    Rainer Ebel
    Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, United Kingdom
    More by Rainer Ebel
  • Fernando Reyes
    Fernando Reyes
    Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Parque Tecnológico de Ciencias de la Salud, E-18016 Granada, Spain
  • Marcel Jaspars*
    Marcel Jaspars
    Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, United Kingdom
    *Mailing address: Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK. E-mail: [email protected]
  • , and 
  • Peter A. M. de Witte*
    Peter A. M. de Witte
    Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium
    *Mailing address: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, Belgium. E-mail: [email protected]
Cite this: ACS Chem. Neurosci. 2018, 9, 7, 1652–1662
Publication Date (Web):April 19, 2018
https://doi.org/10.1021/acschemneuro.8b00060
Copyright © 2018 American Chemical Society

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    Abstract

    Abstract Image

    In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A2, pseurotin F1, 11-O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A2 and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A2 and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A2 and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A2 and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschemneuro.8b00060.

    • 1D NMR data of pseurotin A, pseurotin A2, pseurotin F1, 11-O-methylpseurotin A, pseurotin D, and azaspirofurans A and B (PDF)

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