Simple, Selective Antimitotic Antiparasitic Agents

简单、选择性抗有丝分裂抗寄生虫药

• 批准号: 6813915
• 负责人: KARL A WERBOVETZ
• 金额: $ 35.99万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6813915
• 关键词: Trypanosoma brucei; antiparasitic agents; binding sites; chemical structure function; combinatorial chemistry; computer simulation; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; inhibitor /antagonist; laboratory mouse; leishmaniasis; nitro compounds; nonhuman therapy evaluation; pharmacokinetics; sulfanilamides; trypanosomiasis; tubulin

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.

描述（由申请人提供）：针对针对锥虫病和利什曼病的廉价和有效的药物生长至关重要。寄生虫微管蛋白的特异性抑制剂是已知的抗癌和驱虫药物的药物靶标，作为针对这些疾病的化学治疗候选者，将引起人们的极大兴趣。因此，我们着手测试可以利用小管蛋白作为选择性抗丙糖体和抗抗精神病化疗的靶标的假设。为了支持这一假设，我们的实验室已经确定了NL-ARYL-N4-拨号3，5-二硝基磺胺酰胺是来自利什曼原虫和锥虫的小管蛋白的有效和选择性配体。我们在本系列中最好的化合物在纳米尔浓度下在低微摩尔水平下对布鲁氏菌的体外有效，在低微摩尔水平下对donovani的浓度有效，在IC50浓度下与寄生虫细胞分裂干扰，选择性地阻止了在低微摩尔水平下纯化的Leishmanial Pubulin的体外组装，并在低微摩尔水平上均可使用MAGNERS of MAGNERS ORPARN MAGRESS ORVITION MAGRESS ORPARIN MAMERES，并具有Magners of Magners of Magnserian的含量。为了实现我们在该项目上的长期目标，开发新的抗寄生虫药物以选择性地瞄准动力质体微管蛋白，我们提出了以下具体目的： 1。通过创建由平行合成制备的500多个NL-ARYL-N4-DIALKYL-3,5-二硝基磺胺酰胺的聚焦库来对我们简单的抗源性抗寄生虫的合成优化。还将通过传统的合成方法研究硝基组的替代。 2。对抗寄生虫功效，选择性和抗魔法活性的靶化合物的评估。建立的体外方案将使我们能够有效地选择针对非洲锥虫，美国锥虫和利什曼尼亚的最有希望的抗魔法剂，而动物研究将检查体内抗抗丙糖体功效和有希望化合物的药代动力学。 3。通过计算机建模和新的选择性抗纤维蛋白剂的基于结构的设计来鉴定我们的抗魔法剂的结合位点。这些研究将为我们当前化合物的特异性提供有关分子基础的洞察力，还将提供一个机会，以鉴定具有选择性抗糖性抗寄生虫活性的新型药物，可以作为候选药物。