Validation of New Antimalarial Leads

描述（由申请人提供）：该资助申请的重点是命中铅的研究，将评估一系列命中所产生的细胞高通量筛选，检测抑制剂恶性疟原虫生长在红细胞内阶段。对于每一个新的命中系列，我们将探索结构活性关系，支配效力，细胞选择性和功效;结构属性关系，支配吸附，分布，代谢和排泄;和作用机制。在每一种情况下，研究的目的都是在现有抗疟药物组合和开发候选药物的背景下，评价每个新系列的开发潜力。将根据这些研究对该系列进行优先排序，其中理想系列具有新的作用机制、对疟原虫相对于人类宿主的高固有选择性以及与口服候选药物开发相容的理化性质。因此，该项目是正在进行的MMV支持领先候选开发的完美补充，因为它将为进一步开发提供新的抑制剂类型。该计划的具体目标是：1。通过再合成和有限构效关系研究验证SJCRH筛选中尽可能多的命中。2.对至少5个经验证的命中产品执行命中到潜在客户研究，将其提升到早期潜在客户状态或取消其进一步工作的资格。3.评估每个早期潜在客户的责任，并为其后期发展制定具体计划。 公共卫生相关性：疟疾是现存最严重的人类健康问题之一，全世界每年发病率达数亿例。虽然药物仍然是治疗疟疾感染的主要手段，但无论是从治疗还是从疗效上讲，廉价、有效的药物如氯喹现在都在世界范围内受到耐药性的影响。开发多种新的抗疟化学型是在消灭疟疾运动中最有希望避免抗药性疟疾的战略。

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.