title: Antiplasmodial activities of homogentisic acid derivative protein kinase inhibitors isolated from a Vanuatu marine sponge Pseudoceratina sp.
abstract: As part of our search for new antimalarial drugs in South Pacific marine sponges, we have looked for inhibitors of Pfnek-1, a specific protein kinase of Plasmodium falciparum. On the basis of promising activity in a preliminary screening, the ethanolic crude extract of a new species of Pseudoceratina collected in Vanuatu was selected for further investigation. A bioassay-guided fractionation led to the isolation of a derivative of homogentisic acid [methyl (2,4-dibromo-3,6-dihydroxyphenyl)acetate, 4a] which inhibited Pfnek-1 with an IC(50) around 1.8 muM. This product was moderately active in vitro against a FcB1 P. falciparum strain (IC(50) = 12 muM). From the same sponge, we isolated three known compounds [11,19-dideoxyfistularin-3 (1), 11-deoxyfistularin-3 (2) and dibromo-verongiaquinol (3)] which were inactive against Pfnek-1. Synthesis and biological evaluation of some derivatives of 4a are reported.
authors.affiliation: Laboratoire de Chimie, Université de la Nouvelle-Calédonie, Nouméa cedex, New Caledonia. nicolas.lebouvier@univ-nc.nc
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebouvier
authors.forename: Valérie
authors.initials: V
authors.lastname: Jullian
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desvignes
authors.forename: Séverine
authors.initials: S
authors.lastname: Maurel
authors.forename: Arnaud
authors.initials: A
authors.lastname: Parenty
authors.forename: Dominique
authors.initials: D
authors.lastname: Dorin-Semblat
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
authors.forename: Michel
authors.initials: M
authors.lastname: Sauvain
authors.forename: Dominique
authors.initials: D
authors.lastname: Laurent
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology; D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D057075:Enzyme Assays; D006713:Homogentisic Acid / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011161:Porifera / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D009514:Vanuatu
chemical_list: D000900:Anti-Bacterial Agents; D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D006713:Homogentisic Acid