Identification of Novel antimalarial drugs targeting asexual blood stage of P. Vivax

该项目的目标是确定新的化合物，这些化合物对血液和肝脏阶段的疟疾寄生虫有效，对预防和治疗间日疟原虫和恶性疟原虫感染都有用。疟疾已被确定为对全世界已部署部队的最重大威胁之一。这种疾病流行于包括阿富汗、东南亚、非洲、中东、太平洋以及中美洲和南美洲在内的西南亚。该项目团队此前完成了针对DD2株恶性疟原虫无性血期寄生虫的高通量筛选，在此期间，该团队致力于在体外鉴定在亚微摩尔浓度下选择性抑制伯氏疟原虫肝期寄生虫的化合物。自那以后，已经启动了一项深入的Hit-to-Lead运动，列出了一系列优先的化学类型，目标是识别在体外对恶性疟原虫无性血液阶段和伯氏疟原虫肝脏阶段有效的化合物。潜在的铅分子将被用来评估一次和二次化验中的活性，以及用来评估新陈代谢稳定性、溶解性和膜通透性的药理分析。利用药物化学进一步优化了已鉴定的两种铅化学类型，从而产生了具有更高效力和药代动力学特性的化合物。除了这些最初的活性外，还鉴定了更多具有抗低孢子体阶段活性的化合物(休眠肝脏形式)，验证以及利用目前正在进行的现有类似物的初步构效关系。

The goal of this project is to identify novel chemical compounds that are active against the blood and liver stage forms of malaria parasites and that are useful for both prophylaxis and treatment of Plasmodium vivax and Plasmodium falciparum infections. Malaria has been identified as one of the most significant threats to deployed troops worldwide. This disease is endemic to Southwest Asia including Afghanistan, Southeast Asia, Africa, the Middle East, the Pacific, and both Central and South America. The project team previously completed high-throughput screening more than 400,000 compounds against the Dd2 strain of P. falciparum asexual blood stage parasite, and during this period, the team worked to identify compounds that selectively inhibited P. berghei liver stage parasites in vitro at submicromolar concentrations. An in-depth hit-to-lead campaign has since been initiated with a prioritized list of chemotypes, with the goal of identifying compounds that are potent in vitro against P. falciparum asexual blood stages and P. berghei liver stages. Potential lead molecules will be profiled to assess activity in the primary and secondary assays, as well as in pharmacological profiles to assess metabolic stability, solubility and membrane permeability. Two of the identified lead chemotypes were further optimized using medicinal chemistry leading to compounds with increased potency and pharmacokinetic properties. In addition to these initial hits, additional compounds with activity against the hyponozoite stage (dormant liver forms) have been identified, validation as well as initial structure-activity relationship utilizing existing analogs in currently underway.