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ACS Chem Neurosci. 2018 Jul 18;9(7):1652-1662. doi: 10.1021/acschemneuro.8b00060. Epub 2018 Apr 19.

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

Author information

1
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences , KU Leuven - University of Leuven , 3000 Leuven , Belgium.
2
Marine Biodiscovery Centre, Department of Chemistry , University of Aberdeen , Aberdeen AB24 3UE , Scotland, United Kingdom.
3
Faculty of Pharmacy, Pharmacognosy Department , Beni-Suef University , Beni-Suef 62513 , Egypt.
4
Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Parque Tecnológico de Ciencias de la Salud, E-18016 Granada , Spain.

Abstract

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.

KEYWORDS:

Aspergillus fumigatus; Epilepsy; antiseizure drug discovery; azaspirofuran A; marine drug discovery; pseurotin A2

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