In Vitro Activities of 2,4-Diaminoquinazoline and 2,4-Diaminopteridine Derivatives against

The 50 % inhibitory concentrations (IC50s) of six compounds were <50 nM, and the most potent compound was 2,4-diamino-5-chloro-6-[N-(2,5-dime-thoxybenzyl)amino]quinazoline (compound 1), with an IC50 of 9 nM. The activity of compound 1 was poten-tiated by the dihydropteroate synthase inhibitor dapsone, an indication that these compounds are inhibitors of dihydrofolate reductase. Further studies are warranted to assess the therapeutic potential of this combi-nation in vivo. Inhibition of the synthesis of folate derivatives has been exploited for the development of drugs with activities against Plasmodium falciparum infection. The enzyme target of anti-folates is dihydrofolate reductase (DHFR), which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The latter is an essential cofactor in the synthesis of thymidine, purines, and methionine (10). Inhibitors of DHFR, such as pyrimethamine and chlorcycloguanil, are used in combination with inhibitors of dihydropteroate synthase (DHPS), a second key enzyme o