Validation of New Antimalarial Leads

描述（由申请人提供）：本资助申请侧重于hit-to-lead研究，该研究将评估一系列由细胞高通量筛选产生的hit，该筛选检测到红细胞内恶性疟原虫生长抑制剂。对于每个热门小说系列，我们将探索控制效力、细胞选择性和功效的结构活性关系；控制吸附、分布、代谢和排泄的结构性质关系；以及作用机制。在每一种情况下，这些研究的目的是在现有抗疟疾药物组合和开发候选药物的背景下，评估每个新系列的开发潜力。该系列将根据这些研究进行优先排序，理想的系列具有新的作用机制，对疟原虫对人类宿主的高固有选择性，以及与开发口服候选药物相容的理化性质。因此，该项目是正在进行的MMV支持主要候选开发的完美辅助，因为它将为进一步开发提供新抑制剂类型的管道。该计划的具体目标是：1。通过再合成和有限结构活性关系的研究，尽可能多地从SJCRH筛选中得到验证。2. 对至少5个经过验证的产品进行从产品到产品的研究，要么将其提升至早期领先地位，要么取消其进一步工作的资格。3. 评估每个早期领导的责任，并为其后期发展制定具体计划。

DESCRIPTION (provided by applicant): This grant application focuses on hit-to-lead studies that will evaluate a series of hits arising from a cellular high throughput screen that detected inhibitors of Plasmodium falciparum growth in the intra-erythrocytic stages. For each novel hit series, we will explore structure activity relationships that govern potency, cellular selectivity, and efficacy; structure property relationships that govern adsorption, distribution, metabolism, and excretion; and mechanism of action. In each case, the purpose of the studies is to evaluate the potential for the development of each novel series in the context of the existing portfolio of antimalarial drugs and development candidates. The series will be prioritized based upon these studies with the ideal series having novel mechanism of action, high inherent selectivity for Plasmodium versus the human host, and physiochemical properties that are compatible with development of an orally available drug candidate. As such, the project is a perfect adjunct to ongoing MMV support of lead-candidate development as it will provide a pipeline of new inhibitor types for further development. The specific aims of this program are: 1. To validate by re-synthesis and limited structure activity relationship studies as many hits as possible from the SJCRH screen. 2. To execute hit-to-lead studies on at least 5 validated hits, either progressing them to early lead status or disqualifying them from further work. 3. To assess liabilities for each early lead and develop specific plans for their later development. Public Health Relevance: Malaria is one of the most profound existing human health problems with annual morbidity of several hundred million cases worldwide. Although drugs remain the dominant means for treating malaria infections, both prophylactically and curatively, inexpensive, effective drugs such as chloroquine now suffer from worldwide resistance. The development of multiple novel antimalarial chemotypes is the strategy that offers the most promise for circumventing drug resistant malaria in the campaign for disease eradication.