FOCUSED PARALLEL SYNTHESIS OF DICATION ANTIFUNGAL AGENTS

这些研究是基于我们以前对双阳离子分子抗真菌活性的研究。这些对超过300种双阳离子分子的初步体外研究表明，先导化合物对白色念珠菌和新型隐球菌都具有抑制性和杀真菌性，对这两种生物体的MIC 80 <0.09 g/mg，MFC为0.10 g/ml。研究还表明，这些化合物对烟曲霉、茄病镰刀菌、假丝酵母菌等有一定的抑菌活性。白色念珠菌和氟康唑耐药株。白色念珠菌和C.新人类一个外部实验室证实了我们的体外数据，也表明了抗A。与HeLa细胞相比，烟曲霉的IC 50值小于0.0050 μ g/ml，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存活模型中与氟康唑具有同等活性。上述发现沿着我们对双阳离子化合物的毒理学和药理学的研究清楚地表明，这些分子具有作为抗真菌剂的巨大潜力。目前的提案将通过利用组合化学技术每年合成超过2，400个相关分子并在体外模型中测试这些分子对C的活性来扩展这些初步研究。albicans和A.对THP-1细胞（人单核细胞）的毒性。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特定靶标筛选化合物。将对抗真菌数据进行详细的QSAR和建模研究，这些结果将用于指导拟定文库的扩展、新文库的开发或相关分子的小子集的离树脂合成。最后，选定的分子将在真菌感染的动物模型中进行测试。该提案汇集了一批经验丰富的研究人员，他们在抗菌剂研究方面有着七年多的成功合作。利用组合化学方法建立重点文库，再加上高通量筛选和数据管理，将优化实现本项目目标的群体机会;发现新的抗真菌药物。

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.