Simple, Selective Antimitotic Antiparasitic Agents

描述（由申请人提供）：迫切需要开发廉价有效的抗锥虫病和利什曼病药物。寄生虫微管蛋白的特异性抑制剂是抗癌和驱虫剂的已知药物靶点，作为针对这些疾病的化疗候选物将引起极大的兴趣。因此，我们已经开始测试的假设，微管蛋白可以利用作为选择性抗锥虫和抗利什曼原虫化疗的目标。为了支持这一假设，我们的实验室已经鉴定了N1-芳基-N4-二烷基-3，5-二硝基磺胺作为来自利什曼原虫和锥虫的微管蛋白的有效和选择性配体。本系列中最好的化合物在体外对T。在中纳摩尔浓度下对布氏杆菌和L.在低微摩尔水平下，杜氏锥虫具有两个数量级的体外选择性，在IC 50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的利什曼管蛋白的体外组装，并且对非洲锥虫的体外选择性超过哺乳动物细胞系。为了实现我们在该项目上的长期目标，即开发选择性靶向动质体微管蛋白的新型抗寄生虫药物，我们提出了以下具体目标： 1.通过创建通过平行合成制备的超过500种N1-芳基-N4-二烷基-3，5-二硝基磺胺的集中文库，合成优化我们的简单抗有丝分裂抗寄生虫剂。硝基的取代也将通过传统的合成方法进行研究。 2.评价目标化合物的抗寄生虫功效、选择性和抗有丝分裂活性。建立在体外协议将使我们能够有效地选择最有前途的抗有丝分裂剂对非洲锥虫，美洲锥虫，利什曼原虫，而动物研究将检查在体内抗锥虫的疗效和药代动力学的有前途的化合物。 3.通过计算机建模和基于结构的新型选择性抗微管蛋白剂的设计来鉴定我们的抗有丝分裂剂的结合位点。这些研究将为我们目前的化合物的特异性提供深入的分子基础，也将提供一个机会，以确定具有选择性抗有丝分裂抗寄生虫活性的新药物，可以作为候选药物。

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.