Optimization of novel phenotypic screening hits for treatment of Malaria

项目摘要。 疟疾仍然是最严重的传染病之一，在全球范围内威胁着世界近50%的地区 每年造成40万人死亡，其中大部分是非洲儿童。没有 有效的疫苗和疾病是通过杀虫剂和药物的组合来管理的 治疗和化学预防。寄生虫获得抗药性的无情能力是必要的 保持新的候选药物的持续流水线。我们试图找出新的化学起点 红细胞P期表型筛选抗疟疾新药的发现要点 恶性疟原虫。我们对一个新获得的(2017年)100K化学库进行了高通量筛选 推论由于它是最近购买的，它可能含有以前没有的新的化学空间 已经检查过了。作为命中验证过程的一部分，我们根据以下内容对屏幕中的命中进行优先排序 实验测量：1)对寄生虫对两个细胞系的效力，2)对人类细胞的选择性 LINE，3)化学物质的新颖性，4)寄生虫杀伤率(最好是中等和快速杀灭)和5)体外 ADME的性质包括代谢稳定性和溶解性。我们确定了16个符合我们的 新颖性的目标，并从这些选择了3个系列的热门到领先的化学。其中包括一种哌啶 羧胺系列(Alchm18)，杀灭率适中，起效好(恶性疟原虫3D7 EC50 &lt；100 nm)，并在体外和体内具有很强的ADME性能；一种基于四唑的系列(AlchM3)， 表现出快速的杀灭动力学，以及一种氮杂乙酸酰胺(Alchm17)，具有良好的效力和溶解性。我们已经验证了 通过母体化合物和类似物的合成，所有三个系列的合成策略。目标是 这项建议的目的是对这三个系列进行Hit-to-Lead化学，评估它们的生物学特征， 并进行研究以确定他们的目标。然后，最强的系列将被优先考虑全面销售 优化。我们的Phillips(寄生虫生物学)、Ready(药物化学)和Charman项目团队 (ADME/PK)经验丰富，有长期的合作记录。该项目也将是一个 与疟疾药物合资企业(MMV)合作，世卫组织将提供实物支持和准入 他们的体外和体内寄生虫功效模型和项目监督。在完成这项建议后，我们将 将对三个新化学系列的可开发性有实质性的新见解，我们将验证 另外三个新的抗疟疾目标，我们将取得三种化学物质中最强的一种 系列通过领先的优化，以确定潜在的临床前开发候选者。

Project Summary. Malaria remains one of the most serious infectious diseases, globally threatening nearly 50% of the world population, and leading to >400,000 deaths annually, mostly among young African children. There are no effective vaccines and the disease is managed through a combination of insecticides and drugs for both treatment and chemoprevention. The relentless ability of the parasite to acquire drug resistance necessitates that a continual pipeline of new drug candidates is maintained. We sought to identify novel chemical starting points for the discovery of new anti-malarial drugs by phenotypic screening against erythrocytic stage P. falciparum. We undertook a high-throughput screen of a newly acquired (in 2017) 100K chemical library reasoning that since it was recently purchased it might contain new chemical space that had not been previously screened. As part of our hit validation process we prioritized hits from the screen based on the following experimental measures: 1) potency versus the parasite against two cell lines, 2) selectivity versus a human cell line, 3) novelty of the chemical matter, 4) parasite kill rate (medium and fast kill being desirable) and 5) in vitro ADME properties including metabolic stability and solubility. We identified 16 chemical series that met our objectives of novelty and from these have selected 3 series for hit to lead chemistry. These include a piperidine carboxamide series (Alchm18) that has a moderate rate of kill, good starting potency (P. falciparum 3D7 EC50 <100 nM), and strong starting in vitro and in vivo ADME properties; a a tetrazole-based series (Alchm3) that shows fast kill kinetics, and a an azetidine amide (Alchm17), with good potency and solubility. We have validated synthetic strategies for all three series through synthesis of both the parent compound and analogs. The goal of this proposal is to conduct hit-to-lead chemistry on these three series, to evaluate their biological profiles, and to perform studies to identify their targets. The strongest series will then be prioritized for full scale lead optimization. Our project team of Phillips (parasite biology), Ready (medicinal chemistry) and Charman (ADME/PK) is highly experienced and has a long track record of working together. The project will also be a collaborative effort with the Medicines for Malaria Venture (MMV) who will provide in kind support and access to their in vitro and in vivo parasite efficacy models and project oversight. Upon completion of this proposal we will have substantial new insight into the developability of three new chemical series, we will have validated up to three additional new anti-malarial targets, and we will have progressed the strongest of our three chemical series through lead optimization to identify a potential preclinical development candidate.