The overall goal of the proposed research is to invent and discover new drugs for the treatment of AIDS. A comprehensive approach involving synthetic chemistry, in vitro biological evaluations, and preliminary toxicology and pharmacology will be used to provide compounds ready for in vivo evaluation and a full IND work-up. The primary rationale is to discover compounds which are potent and specific inhibitors of reverse transcriptase. Compounds which serendipitously act by other mechanisms will not be excluded, however, because we shall use a dual ladder of biological evaluation. That is, we shall test all compounds for activity against human immunodeficiency virus (HIV) plus determine if promising compounds act by inhibition of reverse transcriptase. In this way the synthetic chemistry can follow leads to highly selective inhibitors of reverse transcriptase while the biology ensures that compounds acting by other mechanisms are not overlooked. The detailed specific aims by which these objectives will be achieved are provided in the sections for each of the Laboratory Programs.
These aims can be summarized in the following objectives: (i) To synthesize new nucleoside analogs as potential inhibitors of HIV -- Laboratory Program I. (ii) To provide and synthesize thiosemicarbazone analogs as potential inhibitors of HIV -- No cost contribution by Consultant. (iii) To evaluate new nucleosides and thiosemicarbazones for cytotoxicity, activity against HIV, inhibition of target enzymes, effects on immunological parameters and to perform in vitro metabolism studies with active compounds -- Laboratory Program II. (iv) To perform initial, limited toxicologic and pharmacologic studies with a few compounds judged to be the best drug candidates based upon the foregoing in vitro tests -- Laboratory Program III.
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