Laboratoire de Chimie, Université de la Nouvelle-Calédonie, Nouméa cedex, New Caledonia.
Mar Drugs. 2009 Nov 23;7(4):640-53. doi: 10.3390/md7040640.
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.
作为我们在南太平洋海洋海绵中寻找新的抗疟药物的一部分，我们一直在寻找 Pfnek-1 的抑制剂，Pfnek-1 是疟原虫的一种特定蛋白激酶。在初步筛选中表现出有希望的活性的基础上，我们选择了在瓦努阿图采集的一种新的 Pseudoceratina 物种的乙醇粗提取物进行进一步研究。基于生物活性的分级分离得到了一种 homogentisic 酸的衍生物[甲基（2,4-二溴-3,6-二羟基苯基）乙酸酯，4a]，其对 Pfnek-1 的抑制作用的 IC50 约为 1.8 μM。该产物对 FcB1 疟原虫株具有中等体外活性（IC50=12 μM）。从同一种海绵中，我们还分离出三种已知化合物[11,19-二脱氧 fistularin-3（1），11-脱氧 fistularin-3（2）和二溴-verongiaquinol（3）]，它们对 Pfnek-1 没有活性。报道了一些 4a 衍生物的合成和生物评价。
