DISCOVERY OF NOVEL FUNGICIDAL AGENTS

由于公认的全身性真菌病的增加和有害的一面 目前的抗真菌化疗显示出的效果，已经有了一种 对具有良好药代动力学和低成本的新药物的需求日益增加 毒性。我们计划设计基于对两种真菌的抑制作用的药物 酶系统。我们的主要工作将集中在葡聚糖的抑制上 合酶，负责产生必需的细胞壁的酶 葡聚糖(见项目2)。基于改性基质的缓蚀剂和 将按顺序设计、综合和测试“双替代”方法 测定其体内外活性。此外，我们还将 制备葡聚糖合成抑制剂丘脑菌素的类似物 不能从自然产生的物质中获得的。第二种酶 我们将研究的系统是真菌拓扑异构酶，预计将是 对细胞生长至关重要(见项目3)。我们在设计中的经验 细菌(DNA旋转酶)和哺乳动物(TOPO-II)的合成 拓扑异构酶抑制剂及其药代动力学和体内研究 我们将在目前的努力中利用各项活动。我们目前的领先优势 从这些项目中产生了化合物，并将进一步进行修饰和 随着检测方法的出现，扩大了检测范围。

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.