The synthesis of new 2,4-diaminofuro[2,3-d]pyrimidines with 5-biphenyl, phenoxyphenyl and tricyclic substitutions as dihydrofolate reductase inhibitors

Nonclassical 2,4-diamino-5-substituted furo[2,3-d]pyrimidines 4a-i, 5a-b an d 7a-f were synthesized as extended aromatic ring appended analogs of previ ously reported antifolates 1a-b. The extended aromatic system was designed to better interact with a phenylalanine residue (Phe69) of dihydrofolate re ductase from the opportunistic pathogen Pneumocystis carinii to afford pote nt and selective inhibitors of Pneumocystis carinii dihydrofolate reductase . The target compounds were synthesized by nucleophilic displacement of 2,4 -diamino-5-(chloromethyl)furo[2,3-d]pyrimidine 3 with the appropriate aroma tic amine or thiol. The compounds were evaluated as inhibitors of dihydrofo late reductase from Pneumocystis carinii and Toxoplasma gondii, and their s electivity was determined using rat liver dihydrofolate reductase as the ma mmalian reference. In the C8-N9 bridged series, compound 4e, with a 3-(2-me thoxydibenzofuran)- side chain, exhibited greatest potency and was more tha n 3 times as selective for Pneumocystis carinii dihydrofolate reductase com pared to rat liver dihydrofolate reductase. Compounds 4b and 4e also exhibi ted selectivity. Compounds in the C8-S9 bridged series showed comparable po tencies, and each showed higher selectivity for Pneumocystis carinii dihydr ofolate reductase compared to rat liver dihydrofolate reductase.