INSERM U761, Biostructures and Drug Discovery and Faculté de Pharmacie, Université Lille Nord de France, 3 rue du Pr Laguesse, Lille F-59000, France.
J Med Chem. 2012 Dec 27;55(24):10909-17. doi: 10.1021/jm301506h. Epub 2012 Dec 5.
Malaria is a severe infectious disease that causes between 655,000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure-activity relationships of a selective family of hydroxamate PfAM1 inhibitors based on the malonic template. In particular, we performed a "fluoro-scanning" around hit 1 that enlightened the key positions of the halogen for activity. The docking of the best inhibitor 2 is consistent with in vitro results. The stability of 2 was evaluated in microsomes, in plasma, and toward glutathione. The in vivo distribution study performed with the nanomolar hydroxamate inhibitor 2 (BDM14471) revealed that it reaches its site of action. However, it fails to kill the parasite at concentrations relevant to the enzymatic inhibitory potency, suggesting that killing the parasite remains a challenge for potent and druglike catalytic-site binding PfAM1 inhibitors. In all, this study provides important insights for the design of inhibitors of PfAM1 and the validity of this target.
疟疾是一种严重的传染病，每年导致 65.5 万至 120 万人死亡。为了克服对现有药物的耐药性，需要开发新的药物作用靶点。天冬氨酰蛋白酶 M1（PfAM1），一种锌金属蛋白酶，已被提议作为一种新的抗疟药物靶点。在此，我们根据丙二酸模板揭示了一组选择性羟肟酸 PfAM1 抑制剂的结构-活性关系。特别是，我们在命中化合物 1 周围进行了“氟扫描”，阐明了活性的卤原子的关键位置。最佳抑制剂 2 的对接与体外结果一致。在微粒体、血浆和谷胱甘肽中评估了 2 的稳定性。用纳摩尔级羟肟酸抑制剂 2（BDM14471）进行的体内分布研究表明，它到达了作用部位。然而，它未能以与酶抑制效力相关的浓度杀死寄生虫，这表明杀死寄生虫仍然是一个挑战，需要有强效和类药性的催化位点结合 PfAM1 抑制剂。总之，这项研究为 PfAM1 抑制剂的设计提供了重要的见解，并证明了该靶点的有效性。
