Abstract
Nonclassical 2,4βdiaminoβ5βsubstituted furo[2,3βd]pyrimidines 4aβi, 5aβb and 7aβf were synthesized as extended aromatic ring appended analogs of previously reported antifolates 1aβb. The extended aromatic system was designed to better interact with a phenylalanine residue (Phe69) of dihydrofolate reductase from the opportunistic pathogen Pneumocystis carinii to afford potent and selective inhibitors of Pneumocystis carinii dihydrofolate reductase. The target compounds were synthesized by nucleophilic displacement of 2,4βdiaminoβ5β(chloromethyl)furo[2,3βd]pyrimidine 3 with the appropriate aromatic amine or thiol. The compounds were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii, and their selectivity was determined using rat liver dihydrofolate reductase as the mammalian reference. In the C8βN9 bridged series, compound 4e, with a 3β(2βmethoxydibenzofuran)β side chain, exhibited greatest potency and was more than 3 times as selective for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase. Compounds 4b and 4c also exhibited selectivity. Compounds in the C8βS9 bridged series showed comparable potencies, and each showed higher selectivity for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase.