High-potency nitro antimicrobials for topical treatment of trichomoniasis

 描述(申请人提供)：阴道毛滴虫是最常见的非病毒性性传播感染的病原体，全球每年报告约2.5亿例新病例，美国为500万-700万例。除泌尿生殖道感染外 滴虫病会增加不良妊娠结局和艾滋病毒传播的风险，并增加宫颈癌和前列腺癌的发病率和严重程度。只有两种药物被FDA批准用于治疗滴虫病，即硝基杂环化合物甲硝唑(Mz)和替硝唑。在大多数病例中，口服Mz可导致临床和微生物治愈，但极少数患者(高达17%)会出现治疗失败的情况，有报道称Mz的耐药性增加。大剂量口服Mz或替硝唑联合局部用药(S)已成功治疗Mz难治性阴道毛滴虫病，而单用Mz局部治疗仅有少量有效，因此不推荐使用。虽然局部治疗在原则上是可能的，正如在小鼠模型中所显示的那样，而且会很有吸引力，因为与口服制剂相比，较低的全身吸收可能会减少全身不良反应，但目前的药物对这一首选药物还不够有效。 管理路线。鉴于滴虫病的流行及其与多种疾病结局的关联，以及耐药菌株的增加(以及更多耐药性的可能性)，迫切需要开发新的抗滴虫病药物。我们对1,100种新合成的硝基化合物的初步研究提供了令人信服的证据，表明可以在效力和能力完全克服现有耐药性的情况下开发新的硝基药物。这种“下一代”硝基药物具有明显的优势，与任何其他化合物类别相反，这种抗菌剂类别已经被确定为对滴虫病有效和安全。我们新化合物的效力增加，应该可以开发一种局部治疗方法。因此，该项目的总体目标是开发一种新的硝基铅化合物，用于Mz敏感和Mz耐药滴虫病的局部治疗。基于我们之前的数据，我们已经选择了几个最有希望的结构域，现在将在这些域中进行重点的结构探索。新的衍生物将在体外测试对Mz敏感和耐Mz的阴道毛滴虫的活性和效力，在体外测试哺乳动物细胞的细胞毒性和遗传毒性， 并在体内的小鼠阴道滴虫病模型上进行疗效试验。本项目将利用产生的全面生物活性和毒性数据来选择两种无毒化合物，它们在体外具有最高的效力和克服耐药性的能力，并在体内具有良好的效果，作为后续临床前开发一种新的高效化合物用于该项目第二阶段局部治疗滴虫病的领导和支持。

 DESCRIPTION (provided by applicant): Trichomonas vaginalis is the causative agent of the most common, non-viral sexually-transmitted infection with ~250 million new cases reported annually in the world and 5-7 million cases in the U.S. In addition to infections of the urogenital tract, trichomoniasis increases the risk of adverse pregnancy outcomes and HIV transmission, and increases the incidence and severity of cervical and prostate cancers. Only two drugs are FDA-approved for the treatment of trichomoniasis, the nitro-heterocyclic compounds metronidazole (Mz) and tinidazole. Oral dosing leads to clinical and microbiological cure in the majority of cases, but treatment failures occur in a significant fraction of patients (up to 17%), with reports of increasing resistance in the U.S. High oral Mz or tinidazole doses in combination with topical treatment of the same drug(s) have been used with success for Mz-refractory vaginal trichomoniasis, whereas topical Mz treatment alone is only modestly effective and so is not recommended. While topical treatment is possible in principle, as shown in murine models, and would be attractive because low systemic absorption is likely to reduce systemic adverse effects compared to oral formulations, current drugs are not sufficiently potent for this preferred administration route. Given the prevalence of trichomoniasis, its association with multiple disease outcomes, and the increase in drug-resistant strains (as well as the potential for more resistance), development of new antimicrobials against trichomoniasis is an urgent need. Our preliminary studies of >1,100 newly synthesized nitro compounds provide compelling evidence that novel nitro drugs can be developed with marked improvements in potency and the ability to completely overcome existing drug resistance. Such "next-generation" nitro drugs have the distinct advantage that this antimicrobial class, contrary to any other compound class, is already established to be effective and safe against trichomoniasis. The increased potency of our novel compounds should allow development of a topical treatment. Therefore, the project has the overall objective to develop a new lead nitro compound for the topical treatment of Mz-sensitive and Mz-resistant trichomoniasis. Based on our prior data, we have selected several of the most promising structural domains, and will now perform focused structural explorations within these domains. The new derivatives will be tested for activity and potency against Mz-sensitive and Mz- resistant T. vaginalis in vitro, for cytotoxicity and genotoxicity in mammalian cells in vitro, and for efficacy in a murine model of vaginal trichomoniasis in vivo. The comprehensive bioactivity and toxicity data to be generated in this project will be used to select two non-toxic compounds with the best combination of high potency and ability to overcome resistance in vitro, and good efficacy in vivo as lead and back-up for subsequent preclinical development of a novel high-potency compound for the topical treatment of trichomoniasis in phase II of the project.