The overall goal of this project is to prepare, from the novel class of antifungal alkaloids known as sampangines (SAMs), one or more potentially useful drugs for the treatment of certain AIDS-related opportunistic infections (OI). Currently, treatment of OI is often inadequate for a variety of reasons, including the lack of effective antimicrobial therapy. As part of a program to discover prototype antifungal antibiotics from higher plants, a novel alkaloid, 3-methoxysampangine (3-MeO-SAM), was isolated from the West African shrub, Cleistopholis patens. Preliminary studies accomplished to date have provided significant impetus for further, more extensive investigation and development of this novel class of antifungal antibiotics. Thus, we propose herein a series of chemical and biological studies that will provide the information necessary to accomplish the overall goal of developing the most effective drug(s) in this class. This major objective will be accomplished through the following specific aims: (1) Synthesize a series of rationally designed SAM structural analogs for SAR studies. (2) Evaluate the analogs from (1) for in vitro antifungal (Cryptococcus, Candida), antimycobacterial (Mycobacterium intracellulare) and antiviral (Herpes simplex virus type-1) activity. (3) Establish whether the SAMs act by a novel mechanism. (4) Assess the selectivity of the activity of the SAMs. It is anticipated that successful achievement of these specific aims will provide information necessary for the design of a clinically useful drug in this series. Further, if the SAMs are found to act by a novel antifungal mechanism, this could provide the information necessary to design a search for other such agents from natural sources.
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