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全球近50%的人口 这一疾病每年造成40多万人死亡，其中大多数是非洲儿童。没有 有效的疫苗和疾病是通过杀虫剂和药物的组合管理， 治疗和化学预防。寄生虫获得抗药性的无情能力 保持新药候选药物的持续供应。我们试图找出新的化学物质， 通过针对红细胞P期的表型筛选发现新的抗疟疾药物的要点。 恶性疟原虫。我们对新获得的（2017年）100 K化学文库进行了高通量筛选 推理，因为它是最近购买的，它可能含有以前没有的新化学空间， 筛选出作为命中验证过程的一部分，我们根据以下内容对屏幕上的命中进行优先级排序 实验测量：1）针对两种细胞系对抗寄生虫的效力，2）针对人细胞的选择性 线，3）化学物质的新奇，4）寄生虫杀灭率（期望中等和快速杀灭）和5）体外 ADME性质，包括代谢稳定性和溶解性。我们确定了16个化学系列， 新奇的目标，并从这些选择了3个系列的命中导致化学。这些包括哌啶 甲酰胺系列（Alchm 18）具有中等的杀灭率、良好的起始效力（恶性疟原虫3D 7 EC 50 <100 nM），以及强的体外和体内ADME起始性质;基于四唑的系列（Alchm 3）， 显示出快速的杀灭动力学，以及具有良好效力和溶解性的氮杂环丁烷酰胺（Alchm 17）。我们已经验证 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 该提案的一个重要目的是对这三个系列进行命中-铅化学，以评估其生物学特征， 并进行研究以确定其目标。最强的系列将被优先考虑全面领先 优化.我们的项目团队菲利普斯（寄生虫生物学），准备（药物化学）和查曼 (ADME/PK）经验丰富，有着长期的合作记录。该项目也将是一个 与疟疾药物研发公司（MMV）合作，后者将提供实物支持和获取 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 我们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 三种新的抗疟疾靶点，我们将在三种化学物质中最强的一种上取得进展， 系列通过铅优化，以确定潜在的临床前开发候选。

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.