Evaluating Anti-Parasitic Diazocyclobutenes

评估抗寄生虫重氮环丁烯

• 批准号: 10494469
• 负责人: Daniel Charles Whitehead
• 金额: $ 24.78万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494469
• 关键词: Africa South of the Sahara; African Trypanosomiasis; Alkynes; Antiparasitic Agents; Area; Biological; Cells; Centers of Research Excellence; Chagas Disease; Chemistry; Collaborations; Data; Development; Disease; Electrons; Ethers; Evaluation; Exhibits; Future; Genes; Goals; Human; Label; Laboratories; Leishmania; Leishmaniasis; Libraries; Mammalian Cell; Methodology; Morphology; Organic Chemistry; Organism; Parasites; Parasitic infection; Pharmaceutical Preparations; Principal Investigator; Proteomics; RNA Interference; Reaction; Resistance; Route; Sexually Transmitted Diseases; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Trichomonas; Trichomonas vaginalis; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; United States; analog; cellular targeting; cycloaddition; cytotoxicity; fexinidazole; genetic approach; high throughput screening; infection risk; innovation; neglected tropical diseases; novel; novel therapeutic intervention; overexpression; pathogen; programs; screening; side effect

PROJECT SUMMARY/ABSTRACT Human African trypanosomiasis (HAT) is a neglected tropical disease that is endemic to sub-Saharan Africa, where millions are at risk for infection. The disease, which is caused by the eukaryotic pathogen Trypanosoma brucei, is typically fatal if untreated. Several therapeutic strategies are available, but outside of fexinidazole, these drugs are marred by relatively high toxicity, serious side-effects, and emerging resistance. Thus, there is a need for novel therapeutic strategies to treat this disease, and those caused by related organisms such as T. cruzi (American trypanosomiasis) and Leishmania spp. (leishmaniasis). Another protozoan target of our efforts, Trichomonas vaginalis, causes the most prevalent non-viral sexually-transmitted infection in the United States (ca. 3 million cases) with in excess of 120 million cases worldwide. Recently, we discovered a straightforward (one-step) route to synthesize a novel class of compounds, the diazacyclobutenes (DCBs), and we determined that some of them have potent anti-trypanosomal activity. The central goals of this proposal are to further explore the structure- activity relationship of these compounds as anti-trypanosomal agents, to uncover their mode of action in trypanosomes, and to explore their utility against another common parasite, Trichomonas vaginalis. The efforts of this proposal are subdivided into three Aims. Specific Aim 1: To rapidly expand the library of diazacyclobutenes and explore the structure-activity relationships that govern their anti-trypanosomal activity. Specific Aim 2: To uncover the mechanism of action responsible for the observed anti-trypanosomal activity of the diazacyclobutenes. Specific Aim 3: To explore the utility of diazacyclobutenes against the Parabasalid protozoan, Trichomonas vaginalis. Overall, this study will represent the first characterization of diazacyclobutenes as anti-parasitic drugs, while developing the synthetic routes necessary for expansion of this interesting class of compounds. Successful completion of these studies will provide the framework for a future R01 submission that will focus on the development of much needed drugs for parasite infections.

项目概要/摘要 非洲人类锥虫病 (HAT) 是一种被忽视的热带疾病，是撒哈拉以南非洲地区的流行病，其中 数百万人面临感染风险。该疾病由真核病原体布氏锥虫引起， 如果不及时治疗通常会致命。有多种治疗策略可供选择，但除了非昔硝唑之外，这些药物 其缺点是毒性相对较高、副作用严重且耐药性不断出现。因此，需要新颖的 治疗这种疾病以及由相关生物体如克氏锥虫（美国克氏锥虫）引起的疾病的治疗策略 锥虫病）和利什曼原虫属。 （利什曼病）。我们努力的另一个原生动物目标，毛滴虫 阴道念珠菌，引起美国最流行的非病毒性传播感染（约 300 万 例），全球病例数超过 1.2 亿。最近，我们发现了一种直接（一步）的途径 合成了一类新型化合物，二氮杂环丁烯（DCB），我们确定其中一些 具有有效的抗锥虫活性。该提案的中心目标是进一步探索结构- 这些化合物作为抗锥虫药物的活性关系，以揭示它们的作用方式 锥虫，并探索它们对抗另一种常见寄生虫阴道毛滴虫的效用。的努力 该提案分为三个目标。具体目标 1：快速扩大二氮杂环丁烯库 并探索控制其抗锥虫活性的结构-活性关系。具体目标 2： 揭示了所观察到的二氮杂环丁烯抗锥虫活性的作用机制。 具体目标 3：探索二氮杂环丁烯对抗 Parabasalid 原生动物毛滴虫的效用 阴道炎。总的来说，这项研究将首次表征二氮杂环丁烯作为抗寄生虫药物， 同时开发扩展这类有趣的化合物所需的合成路线。成功的 这些研究的完成将为未来 R01 提交提供框架，该框架将重点关注 开发急需的寄生虫感染药物。