Novel Multiple-Stage Active Antimalarials

项目摘要/摘要 值得注意的是，天然产品一直是对抗许多传染性疾病的最前沿的方法 疾病。许多天然产品已经成为设计和开发的模板 目前处于临床或开发阶段的抗疟疾药物。最近，我们开发了一系列 新型抗疟疾化学实体的灵感来自于符合以下条件的Prodiginine和Tambjamin天然产品 以下关键标准：1)有效地防治肝期和血期疟疾寄生虫，以及 抑制配子形成；2)口服有效；3)一剂治愈；4)快速起效；5)持续时间长 覆盖范围；以及6)与现有抗疟疾药物相比的独特化学类型可能由一种新的 作用机制(S)。与感染的多个阶段作斗争的能力，具有传播的潜力 阻塞是一种强大的工具，非常适合作为 新一轮的根除疟疾工作正在进行。我们在本申请中提议的工作旨在开发新的、 预防和治疗疟疾的有效、安全和廉价的抗疟疾药物，从而支持 在世界范围内消除这种疾病。该项目的具体目标是进行领先的优化研究，以 为完整的临床前测试产生领先的候选对象，保留广谱特征并展示 增强的有效性、安全性和药代动力学特征，值得进一步开发。

PROJECT SUMMARY/ABSTRACT Natural products have been notably at the forefront of most approaches to combating many infectious diseases. Many of the natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. Recently we have developed a series of novel antimalarial chemical entities inspired by the prodiginine and tambjamine natural products that meet the following key criteria: 1) potent activities against liver stage and blood stage malaria parasites, as well as inhibition of gamete formation; 2) orally efficacious; 3) curative in a single dose; 4) fast-acting; 5) long duration of coverage; and 6) unique chemotype as compared to existing antimalarials likely operate by a novel mechanism(s) of action. The ability to combat multiple stages of the infection with the potential of transmission blocking represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as a renewed malaria eradication effort proceeds. Our proposed work in this application seeks to develop novel, potent, safe, and inexpensive antimalarial drugs for both prevention and treatment of malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce lead candidates for full preclinical testing that retain the broad-spectrum features and demonstrate enhanced efficacy, safety and pharmacokinetic profiles that warrant further development.