The protozoan parasite Plasmodium falciparum causes the most severe form of human malaria and is estimated to kill 400,000 people a year. The parasite infects and replicates in host red blood cells (RBCs), where it expresses an array of proteases to carry out multiple essential processes. We are investigating the function of falcilysin (FLN), a protease known to be required for parasite development in the RBC. We previously developed a piperazine-based hydroxamic acid scaffold to generate the first inhibitors of FLN, and the current study reports the optimization of the lead compound from that series. A range of substituents were tested at the N1 and N4 positions of the piperazine core, and inhibitors with significantly improved potency against purified FLN and cultured P. falciparum were identified. Computational studies were also performed to understand the mode of binding for these compounds, and predicted a binding model consistent with the biochemical data and the distinctive SAR observed at both the N1 and N4 positions.

原生动物寄生虫恶性疟原虫会导致最严重的人类疟疾，估计每年会导致 400,000 人死亡。寄生虫感染并在宿主红细胞 (RBC) 中复制，在那里它表达一系列蛋白酶以执行多个基本过程。我们正在研究镰刀菌素 (FLN) 的功能，这是一种已知红细胞中寄生虫发育所需的蛋白酶。我们之前开发了一种基于哌嗪的异羟肟酸支架来生成第一个 FLN 抑制剂，目前的研究报告了该系列先导化合物的优化。在哌嗪核心的 N1 和 N4 位置测试了一系列取代基，并鉴定了对纯化的 FLN 和培养的恶性疟原虫具有显着改善效力的抑制剂。