Simple, Selective Antimitotic Antiparasitic Agents

描述（由申请人提供）：迫切需要开发廉价有效的治疗锥虫病和利什曼病的药物。寄生虫微管蛋白的特异性抑制剂是一种已知的抗癌和驱虫药的药物靶点，作为这些疾病的化疗候选药物将引起极大的兴趣。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化疗的靶标的假设。为了支持这一假设，我们的实验室已经鉴定出nl -芳基- n4 -二烷基- 3,5 -二硝基磺胺是利什曼原虫和锥虫微管蛋白的有效和选择性配体。我们在该系列中最好的化合物在体外对中等纳摩尔浓度的布鲁氏t虫和低微摩尔水平的多诺瓦氏l虫有效，在IC50浓度下干扰寄生虫细胞分裂，在低微摩尔水平下选择性地阻断纯化利什曼微管蛋白的体外组装，并且在哺乳动物细胞系中对非洲锥虫具有两个数量级的体外选择性。为了实现我们在这个项目上的长期目标，开发新的抗寄生虫药物，选择性地靶向着丝质体微管蛋白，我们提出以下具体目标：

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.