Novel Multiple-Stage Active Antimalarials

新型多阶段活性抗疟药

• 批准号: 10621341
• 负责人: JANE X KELLY
• 金额: $ 60.28万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621341
• 关键词: Antimalarials; Biological Assay; Blood; Caco-2 Cells; Chemicals; Child; Clinic; Communicable Diseases; Cytochrome P450; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Stability; Drug resistance; Germ Cells; Goals; Hepatocyte; Human; In Vitro; Infection; Isoenzymes; Life Cycle Stages; Liver; Liver Microsomes; Malaria; Malaria Diagnosis; Metabolic; Microsomes; Modeling; Mus; Natural Products; Oral; Parasites; Permeability; Pharmaceutical Preparations; Phase; Plasmodium; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium yoelii; Preclinical Testing; Pregnant Women; Prevention; Relapse; Research; Rodent; Safety; Series; Sporozoites; Time; Toxic effect; Toxicity Tests; Work; bioluminescence imaging; chemical synthesis; combat; cytotoxicity; design; improved; in vivo; iterative design; lead candidate; lead optimization; malaria infection; metabolic profile; natural product inspired; nonhuman primate; novel; prevent; process optimization; prodiginine; relapse prevention; small molecule libraries; tool; transmission blocking

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.

项目总结/摘要 天然产品已明显地处于对抗许多传染病的大多数方法的最前沿。 疾病许多天然产物已作为模板的设计和开发， 目前已进入临床或处于开发阶段的抗疟药物。最近，我们开发了一系列 受符合国际标准的Prodiginine和tambjamine天然产物启发的新型抗疟疾化学实体， 以下关键标准：1）对肝脏期和血液期疟疾寄生虫的有效活性，以及 抑制配子形成; 2）口服有效; 3）单剂量治疗; 4）速效; 5）持续时间长 和6）与现有抗疟药相比，独特的化学型可能通过一种新的 作用机制。能够对抗具有传播潜力的多阶段感染 阻塞是一个强大的工具，它非常适合实现最广泛的利益， 继续开展消除疟疾的努力。我们在本申请中提出的工作寻求开发新颖的， 有效、安全和廉价的抗疟疾药物，用于预防和治疗疟疾，从而支持 在世界范围内消灭这种疾病。该项目的具体目标是进行铅优化研究， 为完整的临床前测试提供领先的候选产品，这些产品保留了广谱特性， 增强的疗效、安全性和药代动力学特征，值得进一步开发。