Evaluating Anti-Parasitic Diazocyclobutenes

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地方病，在那里 数百万人面临感染的风险。这种疾病是由真核病原体布鲁氏锥虫引起的， 如果不治疗，通常是致命的。有几种治疗策略可用，但除了非辛硝唑外，这些药物 被较高的毒性、严重的副作用和新出现的耐药性所破坏。因此，对小说的需求 治疗这种疾病的治疗策略，以及由相关生物引起的治疗策略，如T.ruzi(美国 锥虫病)和利什曼原虫。(利什曼病)。我们努力的另一个原生动物目标是毛滴虫 阴道感染是美国最流行的非病毒性性传播感染(约300万人) 病例)，全世界有超过1.2亿个病例。最近，我们发现了一个简单(一步)的方法来 合成了一类新的化合物，二氮杂环丁烯(DCB)，我们确定了其中的一些化合物 有很强的抗锥虫活性。这项建议的中心目标是进一步探讨以下结构- 这些化合物作为抗锥虫药物的活性关系，以揭示它们在 锥虫，并探索其对另一种常见寄生虫阴道毛滴虫的效用。所做的努力 这项建议细分为三个目标。具体目标1：快速扩大二氮杂环丁烯文库 并探索其抗锥虫活性的构效关系。具体目标2： 揭示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副巴氏原虫滴虫的作用 阴道。总体而言，这项研究将代表二氮杂环丁烯作为抗寄生虫药物的首次表征， 同时开发必要的合成路线，以扩大这类有趣的化合物。成功 这些研究的完成将为未来的R01提交提供框架，该框架将侧重于 开发急需的治疗寄生虫感染的药物。

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.