Tasdemir Deniz, Lack Gabriela, Brun Reto, Rüedi Peter, Scapozza Leonardo, Perozzo Remo
University of Zurich, Institute of Organic Chemistry, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
J Med Chem. 2006 Jun 1;49(11):3345-53. doi: 10.1021/jm0600545.
After the discovery of a potent natural flavonoid glucoside as a potent inhibitor of FabI, a large flavonoid library was screened against three important enzymes (i.e., FabG, FabZ, and FabI) involved in the fatty acid biosynthesis of P. falciparum. Although flavones with a simple hydroxylation pattern (compounds 4-9) showed moderate inhibitory activity toward the enzymes tested (IC50 10-100 microM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 microM). Isoflavonoids 26-28 showed moderate (IC50 7-30 microM) but selective activity against FabZ. The most active compounds were C-3 gallic acid esters of catechins (32, 33, 37, 38), which are strong inhibitors of all three enzymes (IC50 0.2-1.1 microM). Kinetic analysis using luteolin (12) and (-)-catechin gallate (37) as model compounds revealed that FabG was inhibited in a noncompetitive manner. FabZ was inhibited competitively, whereas both compounds behaved as tight-binding noncompetitive inhibitors of FabI. In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range.
在发现一种有效的天然黄酮糖苷作为FabI的有效抑制剂后，针对参与恶性疟原虫脂肪酸生物合成的三种重要酶（即FabG、FabZ和FabI）对一个大型黄酮文库进行了筛选。尽管具有简单羟基化模式的黄酮（化合物4 - 9）对所测试的酶表现出中等抑制活性（IC50为10 - 100 microM），但更复杂的黄酮（12 - 16）对所有三种酶都表现出强活性（IC50为0.5 - 8 microM）。异黄酮26 - 28表现出中等（IC50为7 - 30 microM）但对FabZ具有选择性的活性。活性最高的化合物是儿茶素的C - 3没食子酸酯（32、33、37、38），它们是所有三种酶的强效抑制剂（IC50为0.2 - 1.1 microM）。以木犀草素（12）和（ - ） - 儿茶素没食子酸酯（37）作为模型化合物进行的动力学分析表明，FabG以非竞争性方式被抑制。FabZ被竞争性抑制，而这两种化合物对FabI均表现为紧密结合的非竞争性抑制剂。此外，这些多酚在低至亚微摩尔范围内对氯喹敏感（NF54）和耐药（K1）的恶性疟原虫菌株表现出体外活性。
