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.
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