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As part of our search for new antimalarial drugs, we have screened for inhibitors of Pfnek-1, a protein kinase of Plasmodium falciparum, in south Pacific marine sponges. On the basis of a preliminary screening, the ethanolic crude extract of a new species of Xestospongia collected in Vanuatu was selected for its promising activity. A bioassay-guided fractionation led us to isolate xestoquinone which inhibits Pfnek-1 with an IC(50) around 1 microM. Among a small panel of plasmodial protein kinases, xestoquinone showed modest protein kinase inhibitory activity toward PfPK5 and no activity toward PfPK7 and PfGSK-3. Xestoquinone showed in vitro antiplasmodial activity against a FCB1 P. falciparum strain with an IC(50) of 3 microM and a weak selectivity index (SI 7). Xestoquinone exhibited a weak in vivo activity at 5mg/kg in Plasmodium berghei NK65 infected mice and was toxic at higher doses.

Citation

Dominique Laurent, Valérie Jullian, Arnaud Parenty, Martine Knibiehler, Dominique Dorin, Sophie Schmitt, Olivier Lozach, Nicolas Lebouvier, Maryvonne Frostin, Frédéric Alby, Séverine Maurel, Christian Doerig, Laurent Meijer, Michel Sauvain. Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp. Bioorganic & medicinal chemistry. 2006 Jul 1;14(13):4477-82

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PMID: 16513357

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