Next-generation 5-nitroimidazoles against giardiasis

描述(由申请人提供)： 厌氧原生生物，蓝氏贾第鞭毛虫和溶组织内阿米巴，是肠道B类病原体，每种都会感染全球超过10亿人。它们是可信的生物恐怖主义威胁，因为人类感染所需的包囊不到10个，而且包囊很容易被添加到供水中。两者都会导致正常成年人虚弱的腹泻。有很大的需要改善治疗，因为-15%的贾第鞭毛虫分离株耐药甲硝唑(Mz)，一种5-硝基咪唑(NL)，这是目前的选择药物。由于其相对较高的疗效、安全性和低成本，我们选择使用Mz作为药物发现的先导化合物。我们已经合成了新的5-NI衍生物，对耐Mz的贾第虫具有更高的活性。我们现在将检验这一假设，即位于5-NI核心结构的三个关键位置的新型衍生物将导致可信的候选药物对不同的Mz敏感和Mz耐药的贾第鞭毛虫具有更强的活性。我们将在项目后期将这些发现应用于内阿米巴。我们的具体目标是：目的1.体外鉴定新一代5-NLS，提高其抗Mz敏感和耐Mz贾第鞭毛虫的能力。我们将评估由传统合成有机化学和创新而强大的“点击”化学策略制备的化合物的效力，使用快速初始筛选来确定对贾第虫和内阿米巴具有最高活性的化合物。活动筛选和合成将遵循先导优化的迭代过程。目的2评价精心选择的下一代5-NLS在贾第虫病动物模型中的疗效。我们将评估目标1中确定的最有效的新化合物在小鼠模型中，然后将测试四种最有效的药物治疗猫贾第鞭毛虫病。目的3是确定新的5-NI药物激活和耐药的心血管机制。我们还将开发对新型5-NI化合物具有抗药性的新贾第鞭毛虫品系，并将它们用于AIM 1的进一步药物开发。我们的最终目标是生产至少两种可信的、适合商业使用的新型候选5-NI药物 发展，有效地对抗重要的厌氧病原体，将对世界各地的公共卫生和防御生物恐怖主义有很大的好处。

DESCRIPTION (provided by applicant): The anaerobic protists, Giardia lamblia and Entamoeba histolytica, are enteric Category B pathogens that each infect more than a billion people worldwide. They are credible bioterrorism threats as fewer than ten cysts are needed for human infection and cysts can readily be added to water supplies. Both cause debilitating diarrhea in normal adults. There is a great need for improved treatments as -15% of giardial isolates are resistant to metronidazole (Mz), a 5-nitroimidazole (Nl), that is the current drug of choice. Because of its relatively high efficacy, safety, and low cost, we have elected to use Mz as a lead compound for drug discovery. We have already synthesized new 5-NI derivatives with increased activity against Mz-resistant Giardia. We will now test the hypothesis that novel derivatives at three critical positions of the 5-NI core structure will lead to credible drug candidates with increased activity against diverse Mz-sensitive and Mz-resistant Giardia. We will apply these findings to Entamoeba later in the project. Our Specific Aims are: AIM 1. Identification of next-generation 5-Nls with increased potency against Mz-sensitive and Mz-resistant Giardia in vitro. We will evaluate the potency of compounds prepared by traditional synthetic organic chemistry and by the innovative and powerful "click" chemistry strategy, using rapid initial screens to identify compounds with the highest activity against Giardia and Entamoeba. Activity screens and syntheses will follow an iterative process of lead optimization. AIM 2 is to evaluate the efficacy of carefully selected next generation 5-Nls in animal models of giardiasis. We will evaluate the most potent new compounds identified in Aim 1 in murine models, and will then test the four most efficacious drugs in feline giardiasis. AIM 3 is to define giardial mechanisms of activation of and resistance to new 5-NI drugs. We will also develop new Giardia lines resistant to the novel 5-NI compounds and employ them in further drug development in Aim 1. Our ultimate goal is to produce at least two credible novel candidate 5-NI drugs, suitable for commercial development, that are effective against important anaerobic pathogens and will have great benefit to public health worldwide and to defense against bioterrorism.