FOCUSED PARALLEL SYNTHESIS OF DICATION ANTIFUNGAL AGENTS

双阳离子抗真菌药物的集中平行合成

• 批准号: 6312358
• 负责人: RICHARD TIDWELL
• 金额: $ 50.08万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6312358
• 关键词: Aspergillus; Candida albicans; antifungal agents; biotechnology; chemical structure function; combinatorial chemistry; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; high throughput technology; microorganism culture

The proposed studies stem from our previous research on the antifungal activity of dicationic molecules. These initial in vitro studies on over 300 dication molecules showed that leading compounds were both inhibitory and fungicidal against Candida albicans and Cryptococcus neoformans with MIC80S of <0.09 g/mg and MFCs of 0.10 g/ml against both organisms. Our studies also demonstrated that the compounds were active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans and fluconazole-resistant strains of C. albicans and C. neoformans. An outside laboratory confirmed our in vitro data and also showed that leading compounds against A. fumigatus had IC50 values that were less than 0.0050 mu g/ml and selectivity indices, when compared to HeLa cell, over 2000. More importantly, the outside laboratory demonstrated that one of the compounds was equally as active as fluconazole in a mouse survival model of candidiasis. The above findings along with our studies on the toxicology and pharmacology of dicationic compounds clearly show that these molecules have great potential as antifungal agents. The current proposal will expand these initial studies by synthesizing over 2,400 related molecules per year utilizing combinatorial chemistry technology and testing these molecules in an in vitro model for activity against C. albicans and A. fumigatus and toxcity in THP-1 cell (human monocytes). Since the exact mechanism of antifungal activity is not known, and previous results indicated that more than one mode of action may contribute to their antifungal activity the compounds will be screened against the organism rather than a specific target. The antifungal data will be subjected to detailed QSAR and modeling studies and these results will be used to guide either the expansion of proposed libraries, the development of new libraries, or off resin synthesis of a small subset of related molecules. Finally, selected molecules will be tested in animal models of fungal infections. This proposal brings together a seasoned group of investigators with over seven years of successful collaboration on antimicrobial research. Utilizing the combinatorial chemistry methodology to build focused libraries coupled with high-throughput screening and data management will optimize the groups chances of achieving the goal of this project; the discovery of new antifungal agents.

拟议的研究源于我们之前对双分子抗真菌活性的研究。这些对 300 多种双标记分子的初步体外研究表明，主要化合物对白色念珠菌和新型隐球菌均具有抑制和杀菌作用，对这两种生物体的 MIC80S 小于 0.09 g/mg，MFC 为 0.10 g/ml。我们的研究还表明，这些化合物对烟曲霉、茄病镰刀菌、白色念珠菌以外的念珠菌以及白色念珠菌和新型念珠菌的氟康唑耐药菌株具有活性。外部实验室证实了我们的体外数据，并表明针对烟曲霉的主要化合物的 IC50 值低于 0.0050 μg/ml，与 HeLa 细胞相比，选择性指数超过 2000。更重要的是，外部实验室证明其中一种化合物在念珠菌病小鼠生存模型中与氟康唑具有相同的活性。上述发现以及我们对双药化合物的毒理学和药理学的研究清楚地表明这些分子作为抗真菌剂具有巨大的潜力。目前的提案将利用组合化学技术每年合成 2,400 多种相关分子，并在体外模型中测试这些分子对白色念珠菌和烟曲霉的活性以及对 THP-1 细胞（人单核细胞）的毒性，从而扩大这些初步研究。由于抗真菌活性的确切机制尚不清楚，并且先前的结果表明，不止一种作用模式可能有助于其抗真菌活性，因此将针对生物体而不是针对特定靶标筛选化合物。抗真菌数据将接受详细的 QSAR 和建模研究，这些结果将用于指导拟议库的扩展、新库的开发，或一小部分相关分子的脱树脂合成。最后，选定的分子将在真菌感染的动物模型中进行测试。该提案汇集了一组经验丰富的研究人员，他们在抗菌研究方面拥有七年多的成功合作经验。利用组合化学方法建立重点库，再加上高通量筛选和数据管理，将优化团队实现该项目目标的机会；新抗真菌剂的发现。