DISCOVERY OF NOVEL FUNGICIDAL AGENTS

新型杀菌剂的发现

• 批准号: 3547578
• 负责人: Lester A. Mitscher
• 金额: --
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3547578
• 关键词: antiAIDS agent; antifungal agents; drug design /synthesis /production; drug screening /evaluation; opportunistic infections

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.

由于系统性真菌病的增加和有害的副作用 目前的抗真菌化疗所表现出的效果， 对具有良好的药代动力学和较低的 毒性 我们计划设计基于抑制两种真菌的代理 酶系统 我们的主要工作将集中在抑制葡聚糖 合成酶，负责生产必需的细胞壁的酶 葡聚糖（见项目2）。 基于改性底物的抑制剂和 “双底物”方法将被设计、合成和测试， 以测定它们的体外和体内活性。 此外，我们将 制备葡聚糖合成抑制剂罂粟壳素的类似物， 无法从天然材料中获取。 第二酶 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）。 我们的设计经验 细菌（DNA Gyrase）和哺乳动物（topo-II） 拓扑异构酶抑制剂及其药代动力学和体内研究 将在我们目前的努力中利用这些活动。 我们现在的线索 化合物已经从这些项目中产生，并将进一步修改， 随着测试分析的可用而扩展。

项目成果

DNA topoisomerase inhibitors as antifungal agents.

DNA 拓扑异构酶抑制剂作为抗真菌剂。

• DOI: 10.1016/s1054-3589(08)61140-0
• 发表时间: 1994
• 期刊: Advances in pharmacology (San Diego, Calif.)
• 作者: Shen,LL;Fostel,JM
• 通讯作者: Fostel,JM