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: 7335959
• 负责人: Seth Y Ablordeppey
• 金额: $ 12.25万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335959
• 关键词: DDR; SUBPROJ; BENZOTHIENOQUINOLINES; NOVEL; ANTIFUNGAL

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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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。这项建议的长期目标是在免疫功能低下的个体中确定改进的全身抗真菌药物。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[3,2-b]喹啉和取代吲哚喹啉的类似物。这将提供了解其结构特征和抗真菌活性要求所需的数据，这将使我们能够提高整体抗真菌概况。使用这些药物作为先导化合物的乐观态度源于它们的效力、相对较低的毒性和对与艾滋病和其他免疫功能低下疾病相关的机会性感染（oi）的广谱活性。利用从天然产物cryptolepine类似物中获得的结构信息，我们建议将这些信息纳入设计更有效，毒性更低的化合物，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所提出化合物的三维结构的可视化和比较。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。每个合成的化合物将主要通过1H和13C-NMR和元素分析进行表征，然后使用Sabouraud-dextrose肉汤（SDB）中的两倍连续稀释试验筛选抗真菌活性，用于酵母，新形式C.和烟曲霉或酵母氮肉汤中进行白色念珠菌试验。虽然新生梭菌是结构-活性研究的主要目标，但所有化合物都将对白色梭菌、烟曲霉和酿酒梭菌进行评估，因为这些真菌是引起艾滋病患者和其他免疫功能低下个体各种疾病的致病性真菌。mic小于5 ?的水溶性制剂的细胞毒性谱G /ml将被评估，并选择至少五种具有最佳谱的此类化合物在大鼠模型中进行体内评估。