Simple, Selective Antimitotic Antiparasitic Agents

描述(申请人提供)：迫切需要开发廉价有效的治疗锥虫病和利什曼病的药物。寄生虫微管蛋白是一种已知的抗癌和驱虫药靶标药物，其特异性抑制剂作为治疗这些疾病的候选化疗药物将引起人们的极大兴趣。因此，我们开始测试微管蛋白可以作为选择性抗锥虫和抗利什曼药物化疗靶点的假设。为了支持这一假设，我们的实验室已经确定NL-芳基-N4-二烷基-3，5-二硝基磺胺类化合物是利什曼原虫和锥虫微管蛋白的有效和选择性配体。我们这一系列中最好的化合物在体外对中纳米摩尔浓度的布鲁氏锥虫和低微摩尔水平的杜诺氏锥虫有效，在IC50浓度下干扰寄生虫细胞分裂，在低微摩尔水平选择性阻断纯化的利什曼微管蛋白的体外组装，并且对非洲锥虫细胞株的体外选择性比哺乳动物细胞系高两个数量级。为了实现我们在这个项目上的长期目标，开发选择性靶向动质微管蛋白的新的抗寄生虫药物，我们提出了以下具体目标： 1.通过建立500多个NL-芳基-N4-二烷基-3，5-二硝基-3，5-二硝基磺胺平行合成的聚集库，优化了我们的简单抗寄生虫药的合成。硝基的取代也将通过传统的合成方法进行研究。2.目标化合物的抗寄生虫效果、选择性和抗有丝分裂活性的评价。建立的体外方案将使我们能够有效地选择最有希望的抗非洲锥虫、美洲锥虫和利什曼原虫的抗有丝分裂药物，而动物试验将检验有希望的化合物的体内抗锥虫效果和药代动力学。 3.通过计算机模拟和基于结构的新型选择性抗微管蛋白药物的设计，确定了我们的抗有丝分裂药物的结合部位。这些研究将为我们目前化合物的特异性提供分子基础，并将提供一个机会来确定具有选择性抗有丝分裂抗寄生虫活性的新药物，这些药物可能作为候选药物。

DESCRIPTION (provided by applicant): There is a critical need for the development of cheap and effective drugs against trypanosomiasis and leishmaniasis. Specific inhibitors of parasite tubulin, a known drug target for anticancer and anthelmintic agents, would be of great interest as chemotherapeutic candidates against these diseases. We have thus set out to test the hypothesis that tubulin can be exploited as a target for selective antitrypanosomal and antileishmanial chemotherapy. In support of this hypothesis, our laboratory has identified Nl-aryl-N4- dialkyl-3, 5-dinitro sulfanilamides as potent and selective ligands for tubulin from Leishmania and trypanosomes. Our best compounds in this series are effective in vitro against T. brucei at mid-nanomolar concentrations and against L. donovani at low micromolar levels, interfere with parasite cell division at IC50 concentrations, selectively block the in vitro assembly of purified leishmanial tubulin at low micromolar levels, and possess an in vitro selectivity of two orders of magnitude for African trypanosomes over mammalian cell lines. In attempts toward achieving our long-term goal on this project, to develop new antiparasitic drugs that selectively target kinetoplastid tubulin, we propose the following Specific Aims: 1. Synthetic optimization of our simple antimitotic antiparasitic agents by creating a focused library of over 500 Nl-aryl-N4-dialkyl-3,5-dinitro sulfanilamides prepared by parallel synthesis. Replacement of the nitro groups will also be investigated through traditional synthetic methods. 2. Evaluation of the target compounds for antiparasitic efficacy, selectivity, and antimitotic activity. Established in vitro protocols will allow us to efficiently select the most promising antimitotic agents against African trypanosomes, American trypanosomes, and Leishmania, while animal studies will examine the in vivo antitrypanosomal efficacy and pharmacokinetics of promising compounds. 3. Identification of the binding site of our antimitotic agents through computer modeling and the structure based design of new classes of selective antitubulin agents. These studies will provide insight into the molecular basis for the specificity of our current compounds and will also present an opportunity to identify novel agents with selective antimitotic antiparasitic activity that could serve as drug candidates.