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.

项目摘要/摘要 人类非洲锥虫病（HAT）是一种被忽视的热带疾病，是撒哈拉以南非洲的特有 数百万是有感染的风险。该疾病是由真核病原体Brucei引起的，是 通常未治疗，通常是致命的。可以使用几种治疗策略，但是在Fexinidazole以外，这些药物是 受到相对较高的毒性，严重的副作用和新兴耐药性的伤害。因此，需要小说 治疗这种疾病的治疗策略以及由T. Cruzi等相关生物引起的（美国） 锥虫病）和利什曼尼亚属。 （利什曼病）。我们努力的另一个原生动物目标是 阴道导致美国最普遍的非病毒性传播感染（约300万 案件）全球超过1.2亿个案件。最近，我们发现了一条直接的（一步）通往 合成一类新型化合物，氮囊酸烯烯（DCB），我们确定其中一些 具有有效的抗肌体活动。该提案的核心目标是进一步探索结构 - 这些化合物作为抗牙本质体剂的活动关系，以发现它们的作用方式 锥虫，并探索它们的效用，以抵抗另一个常见的寄生虫阴道。努力 该提议细分为三个目标。特定目的1：快速扩展重物胶烯元的库 并探索控制其抗肌体活动的结构活性关系。具体目标2： 揭示了负责观察到的重物囊核烯的抗肌体活性的作用机理。 特定目的3：探索二氮杂环丁烯对副作用原生动物的效用 阴道。总体而言，这项研究将代表重氮糖酮苯甲作为抗寄生虫药物的首次表征，即 在开发扩展这种有趣类化合物所需的合成路线的同时。成功的 这些研究的完成将为未来的R01提交提供框架，该框架将重点放在 开发急需的寄生虫感染药物。