NEW HETEROCYCLES AND NUCLEOSIDES AS INHIBITORS OF HCMV

该提案概述了开发特异性治疗HCMV感染的药物的几个具体领域。目标化合物将根据我们实验室目前和以前的研究已经建立的结构活性关系进行选择。提出的研究领域和今后四年的具体目标包括：某些D-和L-5 ′-脱氧-5 ′-三氟甲基苯并咪唑核苷的合成，以进一步深入了解这一特定领域的作用方式和构效关系;合成一些吲哚N-核苷和C-核苷，其设计用于增加TCRB样类似物的糖苷稳定性，同时保持抗HCMV的活性; TCRB和BDCRB的特定C-核苷类似物的合成，重点放在增加糖苷键稳定性的结构修饰上;合成选定的TCRB类似物，具有TCRB所表现出的相同独特作用机制的潜力的C-核苷;提供一个设施，以制备更多数量的新先导化合物，用于额外的生物化学和/或作用模式研究;并继续使用我们有限的筛选，包括从我们以前的合成研究中随机选择的化合物，作为重点。 Drach教授和克恩教授实验室的体外评价以及克恩博士实验室的体内评价将用于指导潜在药物在每个新领域的化学修饰。

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.