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

该项目的目标是确定对疟疾寄生虫的血液和肝脏阶段形式具有活性的新型化合物，并可用于预防和治疗间日疟原虫和恶性疟原虫感染。疟疾已被确定为对部署在世界各地的部队的最严重威胁之一。这种疾病在包括阿富汗在内的西南亚、东南亚、非洲、中东、太平洋以及中美洲和南美洲流行。该项目团队之前完成了针对恶性疟原虫无性血液阶段寄生虫Dd 2菌株的40多万种化合物的高通量筛选，在此期间，该团队致力于鉴定在亚微摩尔浓度下体外选择性抑制伯氏疟原虫肝脏阶段寄生虫的化合物。从那时起，已经启动了一项深入的打击铅运动，列出了化学型的优先顺序，目的是鉴定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。将对潜在的铅分子进行分析，以评估一级和二级试验中的活性，以及药理学特征，以评估代谢稳定性、溶解度和膜渗透性。使用药物化学进一步优化了两种鉴定的先导化学型，从而产生具有增加的效力和药代动力学性质的化合物。除了这些最初的命中，其他化合物与活性的次殖子阶段（休眠的肝脏形式）已被确定，验证以及初始结构-活性关系，利用现有的类似物，目前正在进行中。

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.