Department of Chemistry and Biochemistry, California State University, San Bernardino, USA.
Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, USA.
Bioorg Med Chem Lett. 2021 Jan 15;32:127683. doi: 10.1016/j.bmcl.2020.127683. Epub 2020 Nov 20.
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.
疟原虫寄生虫恶性疟原虫可引起最严重的人类疟疾，据估计，每年有 40 万人因此死亡。寄生虫感染和复制在宿主的红细胞（RBC）中，在那里它表达一系列蛋白酶来进行多个必要的过程。我们正在研究裂殖体蛋白酶（FLN）的功能，该蛋白酶已知是寄生虫在 RBC 中发育所必需的。我们之前开发了一种基于哌嗪的偕羟肟酸支架来产生 FLN 的第一种抑制剂，本研究报告了该系列中先导化合物的优化。在哌嗪核心的 N1 和 N4 位置测试了一系列取代基，并鉴定出对纯化的 FLN 和培养的恶性疟原虫具有显著提高的抑制活性的抑制剂。还进行了计算研究以了解这些化合物的结合模式，并预测了与生化数据和在 N1 和 N4 位置观察到的独特 SAR 一致的结合模型。
