(1,2). So long as the numbers of T. gondii infections remained small, there was little impetus to search for improved drugs among the many antifolate agents made more recently. The AIDS epidemic has increased the numbers of T. gondii infections, and the infections in these highly immunosuppressed patients are often severe. As a result, interest in more-potent and less-toxic agents active against T. gondii has also increased.In order to explore the question of whether dihydrofolate reductase inhibitors other than pyrimethamine could be more effective, a broad screen of newer agents was undertaken. A convenient source of compounds for testing was
Sulfanilanilides with 3',5'-halogen substitutions had Ki values 6- to 57-fold lower than the Ki of sulfamethoxazole when tested against dihydropteroate synthase from Toxoplasma gondii. The compounds acted as competitive inhibitors. These compounds were also active against dihydropteroate synthase from Pneumocystis carinii, Mycobacterium avium, and Escherichia coli but were not significantly more active than sulfamethoxazole. The compounds were significantly more active in culture than were standard agents. Against T. gondii in culture, 50% inhibitory concentrations were 7- to 30-fold lower than that of sulfadiazine; against P. carinii in culture, a concentration of 100 microM caused 33 to 95% inhibition of growth, compared with 9% inhibition with 100 microM sulfamethoxazole.
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