Dell'Agli Mario, Parapini Silvia, Galli Germana, Vaiana Nadia, Taramelli Donatella, Sparatore Anna, Liu Peng, Dunn Ben M, Bosisio Enrica, Romeo Sergio
Department of Pharmacological Sciences, School of Pharmacy, University of Milan, Milan 20100, Italy.
J Med Chem. 2006 Dec 14;49(25):7440-9. doi: 10.1021/jm061033d.
The aim of this study was to develop new antiplasmodial compounds acting through distinct mechanisms during both the liver and the blood stages of the parasite life cycle. Compounds were designed on the basis of the "double-drug" approach: primaquine, which has been linked to statine-based inhibitors of plasmepsins (PLMs), the plasmodial aspartic proteases involved in degradation of hemeoglobin. The compounds were tested in vitro for anti-PLM I/PLM II activities and against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum. An antiplasmodial activity (IC(50)) as low as 0.1 microM was obtained, an excellent improvement in comparison with inhibitors previously reported (IC(50) = 2-20 microM). The killing activity was equally directed against both P. falciparum strains and was correlated to lipophilicity (calculated as ALogP), for all compounds but one (9). All compounds inhibited PLM I and PLM II in the nanomolar range (K(i) = 1-700 nM). The most promising compounds (2, 6, 10) were not cytotoxic against human fibroblasts at 100 microM and were highly selective for PLMs vs human cathepsin D.
本研究的目的是开发在疟原虫生命周期的肝脏和血液阶段通过不同机制发挥作用的新型抗疟化合物。化合物基于“双药”方法设计：伯氨喹，它与基于他汀的疟原虫天冬氨酸蛋白酶（PLMs）抑制剂相关，疟原虫天冬氨酸蛋白酶参与血红蛋白的降解。这些化合物在体外测试了抗PLM I/PLM II活性以及对氯喹敏感（D10）和氯喹耐药（W2）的恶性疟原虫菌株的活性。获得了低至0.1微摩尔的抗疟活性（IC50），与先前报道的抑制剂（IC50 = 2 - 20微摩尔）相比有了显著改善。除一种化合物（9）外，所有化合物的杀伤活性对两种恶性疟原虫菌株均有同等作用，且与亲脂性（计算为ALOGP）相关。所有化合物在纳摩尔范围内抑制PLM I和PLM II（K(i) = 1 - 700纳摩尔）。最有前景的化合物（2、6、10）在100微摩尔时对人成纤维细胞无细胞毒性，并且对PLMs与人组织蛋白酶D具有高度选择性。
