Lipophilic diaminopyrimidines are a class of drugs that act as inhibitors of dihydrofolate reductase (DHFR) and have been developed for use as antimalarial, antibiotic, or anticancer agents. These drugs also show striking differences in their inhibitory activity with only small changes in their chemical structure.'- It has been demonstrated that the principal structural characteristic necessary for binding to dihydrofolate reductase of any species is a 2,4-diaminopyrimidine, s-triazine, or pteridine ring structure. Structure-activity studies of 2,4-diaminopyrimidines further indicate that a lipophilic group at position five is also essential for tight binding to DHFR.5 Large differences in inhibitory potency have been observed concomitant with small changes in the chemical structures of these antifolate drug.