Next-generation 5-nitroimidazoles against giardiasis

描述（由申请人提供）： 厌氧原生生物，贾第鞭毛虫和溶组织内阿米巴，是肠道B类病原体，每一种都感染了全世界超过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，并且包囊可以很容易地添加到供水中。这两种疾病都会导致正常成年人腹泻。非常需要改进的治疗，因为约15%的心内膜分离株对甲硝唑（Mz）（一种5-硝基咪唑（NI））具有抗性，甲硝唑是目前的选择药物。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，其对Mz抗性贾第虫的活性增加。我们现在将测试的假设，在3个关键位置的5-NI核心结构的新衍生物将导致可靠的候选药物与不同的Mz敏感和Mz抗性贾第虫的活性增加。我们将在项目的后期将这些发现应用于内阿米巴。我们的目标是：目标1。体外鉴定具有针对Mz敏感性和Mz抗性贾第虫的增加的效力的下一代5-N1。我们将评估通过传统的合成有机化学和创新的和强大的“点击”化学策略制备的化合物的效力，使用快速初始筛选来鉴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一个迭代的过程中导致优化.目的2是评价精心选择的下一代5-N1在贾第虫病动物模型中的功效。我们将在小鼠模型中评估目标1中鉴定的最有效的新化合物，然后将测试猫贾第虫病中最有效的四种药物。目的3：阐明5-硝基水杨酸（5-NI）新药的心血管激活和耐药机制.我们还将开发对新型5-NI化合物具有抗性的新贾第虫品系，并将其用于目标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新型候选5-NI药物，适用于商业化。 这些新技术的开发将有效对抗重要的厌氧病原体，并将对全球公共卫生和防范生物恐怖主义大有裨益。

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.