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.
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