Evaluating Anti-Parasitic Diazocyclobutenes

项目总结/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， 数百万人面临感染风险。这种疾病是由真核病原体布氏锥虫引起的， 如果不治疗通常是致命的。有几种治疗策略可用，但除了非昔硝唑，这些药物 其毒性相对较高，副作用严重，并出现耐药性。因此，需要一种新颖的 治疗策略，以治疗这种疾病，以及那些由相关的生物体，如T。cruzi（美国 锥虫属）和利什曼原虫属（Leishmania spp.）（利什曼病）。我们努力的另一个原生动物目标，毛滴虫 迷走神经病，导致美国最流行的非病毒性传播感染（约。3百万 病例），全球病例超过1.2亿例。最近，我们发现了一个简单的（一步）路线， 合成了一类新的化合物，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。本提案的中心目标是进一步探讨结构- 这些化合物作为抗锥虫剂的活性关系，以揭示它们在 锥虫，并探讨其对另一种常见的寄生虫，阴道毛滴虫的效用。的努力 这一建议分为三个目标。具体目标1：快速扩充二氮杂环丁烯文库 并探索控制其抗锥虫活性的结构-活性关系。具体目标2： 揭示了二氮环丁烯类化合物的抗锥虫活性的作用机制。 具体目标3：探索二氮杂环丁烯类化合物对副基目原生动物毛滴虫的效用 流浪汉总的来说，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， 同时开发了扩展这类令人感兴趣的化合物所必需的合成路线。成功 这些研究的完成将为未来的R 01提交提供框架， 开发急需的寄生虫感染药物。

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.