NEW HETEROCYCLES AND NUCLEOSIDES AS INHIBITORS OF HCMV

该提案概述了开发专门治疗人巨细胞病毒感染的试剂的几个具体领域。目标化合物将根据我们实验室目前和以前的研究中已经建立的构效关系来选择。建议的研究领域和今后四年的具体目标包括：合成某些D-和L-5‘-脱氧-5’-三氟甲基苯并咪唑核苷，以进一步了解这一特定领域的作用方式和构效关系；合成一些吲哚类N-核苷和C-核苷，旨在增加TCRB类似物的糖苷稳定性，同时保持对HCMV的活性；合成TCRB和BDCRB的特定C-核苷类似物，重点是结构修饰，以增加糖苷键的稳定性；合成选定的TCRB类似物，C-核苷，可能具有与TCRB相同的独特作用机制；为制备更多新的先导化合物提供设施，用于额外的生化和/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。来自Drach教授和Kern教授实验室的体外评估，以及Kern博士实验室的体内评估，将被用于指导潜在药物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.