DDR SUBPROJ 2:BENZOTHIENOQUINOLINES AS NOVEL ANTIFUNGAL AGENTS IN AIDS-RELATED

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该提案是密西西比大学和佛罗里达A&M大学药学院PI之间的合作努力。该提案的长期目标是确定免疫功能低下个体的改善的全身性抗真菌药物。然而，当前的重点是使用药物设计技术来提出、合成和评价5-甲基苯并噻吩并[3，2-B]喹啉和取代吲哚并喹啉的类似物。这将提供了解其抗真菌活性的结构特征和要求所需的数据，这将使我们能够改善整体抗真菌特征。使用这些药物作为先导化合物的乐观态度来自于它们的效力、相对低的毒性和对与AIDS和其他免疫受损状况相关的机会性感染（OI）的广谱活性。使用天然产物，cryptolepine的类似物上获得的结构信息，我们建议将这些信息纳入设计更有效和毒性更小的化合物作为替代品两性霉素B和氟胞嘧啶（5-FC）。计算机图形显示将有助于可视化和比较所提出的化合物的3-D结构。活性类似物方法将用于鉴定和选择与抗真菌活性相关的药效基团。每种合成化合物将主要通过1H & 13 C-NMR和元素分析来表征，然后使用沙氏葡萄糖肉汤（SDB）中的两倍连续肉汤稀释测定法对酵母、C. neoformans和A.烟曲霉或酵母氮肉汤培养。白色念珠菌测定。虽然C.由于新型隐球菌是结构-活性研究的主要目标，所有化合物将针对C. albicans、A. fumigatus和C.酿酒酵母，因为这些是引起AIDS患者和其他免疫功能低下个体的各种疾病的病原性真菌群。MIC小于5的水溶性试剂的细胞毒性概况？g/ml，并选择至少五种具有最佳特性的此类化合物用于大鼠模型中的体内评价。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal is a collaborative effort between the University of Mississippi and the PI at Florida A&M University College of Pharmacy. The long-term goal of this proposal is to identify improved systemic antifungal agents in immunocompromised individuals. The immediate focus, however, is to use drug design techniques to propose, synthesize and evaluate analogs of 5-methyl benzothieno[3,2-b]quinoline and substituted indoloquinolines. This will provide the data needed to understand the structural characteristics and requirements for their antifungal activities, which would enable us to improve the overall antifungal profile. Optimism to use these agents as lead compounds derive from their potency, relatively low toxicity and a broad spectrum of activity against opportunistic infections (OIs) associated with AIDS and other immunocompromised conditions. Using structural information obtained on analogs of the natural product, cryptolepine, we propose the incorporation of such information into the design of more potent and less toxic compounds as alternatives to Amphotericin B and Flucytosine (5-FC). Graphical computer displays will aid visualization and comparison of the 3-D structures of the proposed compounds. The active-analog approach will be utilized in the identification and selection of pharmacophoric groups associated with antifungal activity. Each synthetic compound will be characterized primarily by 1H & 13C-NMR and elemental analysis, and then screened for antifungal activity using a two-fold serial broth dilution assay in Sabouraud-dextrose broth (SDB) for yeast, C. neoformans and A. fumigatus or yeast nitrogen broth for C. albicans assays. Although C. neoformans is the primary target for the structure-activity studies, all the compounds will be evaluated against C. albicans, A. fumigatus and C. cerevisiae as these are among the group of pathogenic fungi causing various ailments in AIDS patients and other immunocompromised individuals. The cytotoxicity profile of water-soluble agents with MICs less than 5 ?g/ml will be evaluated and at least five of such compounds with the best profiles will be selected for in vivo evaluation in a rat model.