STRUCTURE ACTIVITY STUDIES OF NOVEL ANTIFUNGAL AGENTS AGAINST OI ASSOC W/ AIDS

该提案的长期目标是发展系统性的 具有最小毒性和优选的抗真菌能力的抗真菌剂， 是口服的 然而，当前的重点是研究 天然产物的构效关系（SAR）， 为了了解其结构特征 以及对其抗真菌活性的要求。 Cryptolepine是 选择它是因为它的效力，水溶性，低毒性， 广谱抗机会性感染 艾滋病 几种结构类似物的cryptolepine将 合成来描述喹多啉的结构特征 核，有助于活动和任何毒性相关的 流毒 这些信息将被纳入 计算机辅助药物设计更有效和毒性更低的化合物 作为两性霉素B和5-氟胞嘧啶（5-FC）的替代品。 图形化的计算机显示将有助于可视化和比较的t 所提出的化合物和其他化合物的三维结构 具有类似活性的天然产物。 主动模拟方法 将用于鉴定和选择药效学 与抗真菌活性相关的组。 每种合成化合物 将通过光谱和元素分析进行表征， 然后相对于C进行评估。neoformans，A. Fumigatus，M.细胞内 和C.白念珠菌使用标准的体外抗真菌试验。 有前途 随后将对新化合物的物理化学性质进行评价， 特征，即，pKa和Log P值，然后是体内活性 以及动物模型中的毒性。

The long-term goal of this proposal is to develop systemic antifungal agents with minimal toxicity and preferable capabilities of being delivered orally. The immediate focus,.however, is to study the structure-activity relationship (SAR) of the natural product, Cryptolepine, in order to understand the structural characteristics and requirements for its antifungal activity. Cryptolepine was selected because of it's potency, water solubility, low toxicity and broad spectrum of activity against opportunistic infections associated with AIDS. Several structural analogues of cryptolepine will be synthesized to delineate the structural features int eh quindoline nucleus that contribute to activity and any toxicities associated with the drug. This information will be incorporated into a computer-assisted drug design of more potent and less toxic compounds as alternatives to Amphotericin B and 5-Fluorocytosine (5-FC). Graphical computer displays will aid visualization and comparison of t he 3-dimensional structures of the proposed compounds and other natural products with similar activity. 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 spectroscopically and by elemental analysis, and then evaluated against C. neoformans, A. Fumigatus, M. Intracellular and C. Albicans using standard in-vitro antifungal assays. Promising new compounds will subsequently be evaluated for their physicochemical characteristics, i.e., pKa and Log P values, and then in vivo activity and toxicity in animal models.