Novel Multiple-Stage Active Antimalarials

新型多阶段活性抗疟药

• 批准号: 10402789
• 负责人: JANE X KELLY
• 金额: $ 61.63万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402789
• 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 resistance; Erythrocytes; Germ Cells; Goals; Hepatocyte; Human; In Vitro; Infection; Isoenzymes; Life Cycle Stages; Liver; Liver Microsomes; Malaria; Malaria Diagnosis; Metabolic; 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; nonhuman primate; novel; prevent; process optimization; prodiginine; small molecule libraries; tool; transmission process

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.

项目摘要/摘要 天然产品特别是大多数方法来打击许多传染性的方法的最前沿 疾病。许多天然产品已成为设计和开发的模板 目前在诊所或开发阶段中的抗疟药。最近，我们开发了一系列 新型抗疟疾化学实体灵感受到质合氨酸和Tambjamine天然产品的启发 遵循关键标准：1）针对肝脏阶段和血液阶段疟疾寄生虫的有效活动，以及 抑制配子形成； 2）口头有效； 3）单剂量治愈； 4）快速行动； 5）长时间 覆盖范围； 6）与现有的抗疟药相比，独特的化学型可能是通过新颖的 作用机制。与传播的潜力对抗多个感染的多个阶段的能力 阻止代表了一个强大的工具，并且非常适合实现最广泛的收益作为一个 重新消除疟疾的努力进行。我们在此应用程序中提出的工作旨在发展小说， 有效，安全且廉价的抗疟药用于预防和治疗疟疾，从而支持 全球消除该疾病。该项目的具体目标是进行铅优化研究 生产铅候选者进行全面临床前测试，以保留广谱特征并演示 增强的功效，安全性和药代动力学特征需要进一步发展。