Mechanism of action antifolate drugs

Sulfonamides act as antimetabolites of PABA and block folic acid synthesis in certain protozoans by inhibiting dihydropteroate synthase. Proguanil (chloroguanide) is bioactivated to cycloguanil. Pyrimethamine and cycloguanil are selective inhibitors of protozoan dihydrofolate reductases. The combination of pyrimethamine with sulfadoxine has synergistic antimalarial effects through the sequential blockade of 2 steps in folic acid synthesis (see Figure 46-1).