.) The overall goal of the proposed work is the discovery of new agents against PC and TG infections, two life-threatening opportunistic diseases associated with AIDS and AIDS-related complex (ARC). More specifically, this project will focus on the design and synthesis of novel dicyclic and tricyclic diaminopyrimidine ring systems structurally related to the lipophilic dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMX) and piritrexim (PTX). TMX and PTX have been found recently to have promising activity against PC and TG when given with folinic acid (FA) to protect host tissues from antifolate toxicity, and may offer some advantages over older antifolate drugs such as trimethoprim and the sulfonamides. Compounds to be synthesized in this project will include six general types of condensed diaminopyrimidine ring systems, and initial emphasis in each group will be on analogs with at least two methoxy groups in the aryl moiety, since this pattern already exists in TMX and PTX. However, the synthetic schemes will be general enough to allow preparation of congeners with other ring substituents, including, for example, halogens. Target compounds will be evaluated for their ability to inhibit DHFR mammalian cell and from PC and TG to determine whether selectivity is shown for either of the parasite enzymes. The compounds will also be tested for the ability to inhibit PC and TG proliferation in rat lung fibroblast monolayer culture in the presence of folinic acid. If any compound shows enough activity and selectivity in these in vitro assays, it will be re-synthesized on a larger scale to provide enough material for subsequent in vivo pharmacological and toxicological studies in mice or other animals.
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