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

DDR 子项目 2：苯并噻吩并喹啉作为艾滋病相关的新型抗真菌剂

• 批准号: 7715247
• 负责人: Seth Y Ablordeppey
• 金额: $ 25.84万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715247
• 关键词: Acquired Immunodeficiency Syndrome; Amphotericin B/Flucytosine; Antifungal Agents; Biological Assay; Biological Factors; Candida albicans; Characteristics; Computer Retrieval of Information on Scientific Projects Database; Computers; Condition; Data; Drug Design; Evaluation; Florida; Flucytosine; Funding; Glucose; Goals; Grant; Imagery; Immunocompromised Host; Individual; Institution; Lead; Mississippi; Modeling; Nitrogen; Opportunistic Infections; Patients; Pharmacy facility; Poison; Rattus; Research; Research Personnel; Resources; Source; Structure; Techniques; Toxic effect; United States National Institutes of Health; Universities; Water; Yeasts; analog; college; cryptolepine; cytotoxicity; design; fungus; improved; in vivo; novel; optimism; quinoline; three dimensional structure

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案是密西西比大学和佛罗里达农工大学药学院 PI 之间的合作成果。该提案的长期目标是在免疫功能低下的个体中找到改进的全身抗真菌药物。然而，当前的焦点是使用药物设计技术来提出、合成和评估 5-甲基苯并噻吩并[3,2-b]喹啉和取代的吲哚喹啉的类似物。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性。使用这些药物作为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针对与艾滋病和其他免疫功能低下病症相关的机会性感染（OIs）的广谱活性。利用从天然产物 Cryptolepine 类似物获得的结构信息，我们建议将这些信息纳入更有效、毒性更小的化合物的设计中，作为两性霉素 B 和氟胞嘧啶 (5-FC) 的替代品。图形计算机显示器将有助于对所提出的化合物的 3D 结构进行可视化和比较。活性模拟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 和 13C-NMR 和元素分析进行​​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筛选抗真菌活性，用于酵母、新型隐球菌和烟曲霉或酵母氮肉汤用于白色念珠菌测定。虽然新型念珠菌是结构活性研究的主要目标，但所有化合物都将针对白色念珠菌、烟曲霉和酿酒酵母进行评估，因为这些都是引起艾滋病患者和其他免疫功能低下个体各种疾病的病原真菌。将评估 MIC 小于 5 μg/ml 的水溶性药物的细胞毒性特征，并选择至少五种具有最佳特征的此类化合物用于大鼠模型的体内评估。