Validation of New Antimalarial Leads

描述(由申请人提供)：这项资助申请侧重于Hit-to-Lead研究，该研究将评估一系列由细胞高通量筛查产生的Hit-to-Lead研究，该筛查在红细胞内阶段检测到恶性疟原虫生长的抑制物。对于每个新的热门系列，我们将探索支配效力、细胞选择性和功效的结构活性关系；支配吸附、分布、新陈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，研究的目的都是评估在现有的抗疟疾药物和开发候选药物组合的背景下开发每个新系列的潜力。该系列将在这些研究的基础上优先考虑，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口服候选药物的开发相兼容的物理化学性质。因此，该项目是对正在进行的领先候选开发的MMV支持的完美补充，因为它将为进一步的开发提供一系列新的抑制剂类型。该计划的具体目标是：1.通过重新合成和有限的结构活性关系来验证从SJCRH屏幕上尽可能多地研究命中。2.对至少5个有效的命中进行命中到领先的研究，要么使它们进入早期领先状态，要么取消它们在进一步工作中的资格。3.评估每个早期销售线索的负债情况，并为其以后的发展制定具体计划。 与公共卫生相关：疟疾是现存的最严重的人类健康问题之一，全世界每年的发病率达数亿例。尽管药物仍然是治疗疟疾感染的主要手段，无论是预防还是治疗，但廉价、有效的药物，如氯喹，现在受到世界范围的抗药性。开发多种新的抗疟疾化学类型是在根除疾病的运动中为规避抗药性疟疾提供最大希望的战略。

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.