NEW HETEROCYCLES AND NUCLEOSIDES AS INHIBITORS OF HCMV

作为 HCMV 抑制剂的新杂环和核苷

• 批准号: 6651244
• 负责人: LEROY B. TOWNSEND
• 金额: $ 15.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651244
• 关键词: antiviral agents; chemical structure; cytomegalovirus; drug design /synthesis /production; heterocyclic compounds; nuclear magnetic resonance spectroscopy; nucleoside analog

This proposal outlines several specific areas for the development of an agent to specifically treat HCMV infections. The target compounds will be selected on the basis of structure activity relationships which have already been established from current and previous studies in our laboratory. The areas of research proposed and the specific aims for the next four years include the following: the synthesis of certain D- and L- 5'-deoxy-5'- trifluoromethyl benzimidazole nucleosides in an effort to further our insight into the mode of action and structure activity relationships in this specific area; the synthesis of some indole N-nucleosides and C- nucleosides designed to increase the glycosidic stability of TCRB-like analogs while maintaining the activity against HCMV; the synthesis of specific C-nucleoside analogs of TCRB and BDCRB, with the emphasis being placed on structural modifications that would increase the stability of the glycosidic bond; synthesis of selected TCRB analogs, C-nucleosides with the potential for the same unique mechanism of action exhibited by TCRB; to provide a facility for the preparation of larger quantities of new lead compounds for additional biochemical and/or mode of action studies; and to continue the use of our limited screen involving compounds selected at random from our previous synthetic investigations, as a focal point. The in vitro evaluations from Professors Drach and Kern's laboratories, and the in vivo evaluations in Dr. Kern's laboratory, will be used to direct the chemical modifications in each new area pf potential agents.

该提案概述了开发代理的几个特定领域，以专门治疗HCMV感染。目标化合物将根据结构活动关系选择，这些关系已经从我们实验室的当前和以前的研究中确定。提出的研究领域以及未来四年的具体目的包括以下内容：综合某些D-和L-5'-脱氧-5'-三氟甲基苯咪唑核苷核苷，以进一步洞悉我们对该特定领域中的作用和结构活性关系的洞察力；某些吲哚N-核苷和C-核苷的合成旨在提高TCRB样类似物的糖苷稳定性，同时保持对HCMV的活性。 TCRB和BDCRB的特异性C-核苷类似物的合成，重点放在结构修饰上，以增加糖苷键的稳定性；选定的TCRB类似物，C-核苷的合成，具有TCRB所表现出相同独特作用机理的潜力；为准备大量新的铅化合物提供设施，以进行其他生化和/或行动方式研​​究；并继续使用有限的屏幕，涉及从我们以前的合成研究中随机选择的化合物作为焦点。 Drach教授和Kern实验室的体外评估以及Kern博士实验室中的体内评估将用于指导每个新区域PF潜在药物中的化学修饰。