Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp.
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.
Laurent
Dominique
D
UMR152 IRD--Université Paul Sabatier Toulouse III, Pharmacochimie des Substances Naturelles et Pharmacophores Redox, Centre IRD, BPA5, Nouméa, New Caledonia. dominique.laurent@noumean.ird.nc
Jullian
Valérie
V
Parenty
Arnaud
A
Knibiehler
Martine
M
Dorin
Dominique
D
Schmitt
Sophie
S
Lozach
Olivier
O
Lebouvier
Nicolas
N
Frostin
Maryvonne
M
Alby
Frédéric
F
Maurel
Séverine
S
Doerig
Christian
C
Meijer
Laurent
L
Sauvain
Michel
M
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001681:Biological Assay; D020128:Inhibitory Concentration 50; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011809:Quinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D047131:Xestospongia / Q000378:metabolism
D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D011809:Quinones; C068501:xestoquinone