DISCOVERY OF NOVEL FUNGICIDAL AGENTS

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Due to the recognized increase in systemic mycoses and the deleterious side effects exhibited by current anti- fungal chemotherapy, there has been an increasing need for new agents with good pharmacokinetics and lower toxicity. We plan to design agents based on the inhibition of two fungal enzyme systems. Our major effort will focus on inhibition of glucan synthase, the enzyme responsible for production of the requisite cell wall glucan (see Project 2). Inhibitors based on modified substrate and "bisubstrate" approaches will be designed, synthesized, and tested in order to determine their in vitro and in vivo activity. Furthermore, we will prepare analogs of the glucan synthesis inhibitor papulacandin which are not accessible from the naturally occurring material. The second enzyme system we will study is fungal topoisomerase, which is expected to be essential for cell growth (see Project 3). Our experiences in the design and synthesis of bacterial (DNA Gyrase) and mammalian (topo-II) topoisomerase inhibitors and study of their pharmacokinetics and in vivo activities will be utilized in our present effort. Our present lead compounds have arisen from these projects and will be further modified and expanded as test assays become available.