In vitro antimalarial activity of tetrahydrofolate dehydrogenase inhibitors

Three tetrahydrofolate dehydrogenase (dihydrofolate reductase = EC 1.5.1.3) inhibitors were tested for antimalarial activity against Plasmodium falciparum, using an in vitro radioisotopic technique. Activity of each drug was tested in both normal RPMI medium 1640 and in modified medium (containing no p-aminobenzoic acid and 2.27 X 10(-8) M folic acid) after a 24- or 48-hour exposure. Activity was increased 20- to 85-fold using the modified medium and the longer exposure time. Under all conditions, pyrimethamine and cycloguanil were of equal or greater potency than an experimental pyrimethamine analogue, M&B 35769, against pyrimethamine-sensitive strains, but M&B 35769 was more active than either pyrimethamine or cycloguanil against pyrimethamine-resistant strains.