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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项提案是密西西比大学和佛罗里达农工大学药学院PI之间的合作努力。这项建议的长期目标是在免疫功能低下的个体中识别改进的系统性抗真菌药物。然而，当前的焦点是利用药物设计技术来提出、合成和评价5-甲基苯并[3，2-b]喹啉和取代吲哚喹啉的类似物。这将为了解它们的结构特征和抗真菌活性的要求提供所需的数据，这将使我们能够改善整体抗真菌概况。将这些药物用作先导化合物的乐观情绪源于它们的效力、相对较低的毒性以及对抗与艾滋病和其他免疫损害相关的机会性感染(OIS)的广泛活性。利用从天然产物隐孢子碱的类似物上获得的结构信息，我们建议将这些信息纳入到更有效和毒性更低的化合物的设计中，作为两性霉素B和氟胞嘧啶(5-FC)的替代品。图形计算机显示将有助于可视化和比较所提议的化合物的三维结构。活性类比方法将被用于识别和选择与抗真菌活性相关的药理活性基团。每个合成化合物将首先通过1H&13C-核磁共振和元素分析进行表征，然后在沙堡-葡萄糖肉汤(SDB)中使用两次连续肉汤稀释法筛选抗真菌活性，以检测酵母菌、新生葡萄球菌和烟曲霉菌或酵母氮源肉汤中的白色念珠菌。虽然结构-活性研究的主要目标是新生葡萄球菌，但所有化合物都将被评估对白色念珠菌、烟曲霉菌和酿酒酵母的作用，因为这些都是导致艾滋病患者和其他免疫功能低下者各种疾病的病原真菌群。将对MIC值小于5g/ml的水溶性药物的细胞毒性谱进行评估，并将选择至少5种具有最佳谱的此类化合物在大鼠模型中进行体内评估。

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.