Folic Acid Metabolism Inhibitors

Folate carries one-carbon units for glycine, purine and thymidylate synthesis, and bacteria and protozoa must make it rather than take it up. Two enzymes of that pathway are drug targets, one step apart. Dihydropteroate synthase condenses para-aminobenzoate with 6-hydroxymethyl-7,8-dihydropterin diphosphate to form 7,8-dihydropteroate - step 1 of the 2-step sub-pathway that ends in dihydrofolate - and sulfonamides such as sulfamethoxazole are competitive inhibitors of it. Dihydrofolate reductase then reduces dihydrofolate to the active tetrahydrofolate, the single step of its own sub-pathway, and is the target of the diaminopyrimidines. This is the parent class for drugs blocking either step, and it is why a sulfonamide and a diaminopyrimidine are combined in one product. As MED-RT populates the class, however, it holds only the dihydrofolate reductase side - trimethoprim, pyrimethamine, proguanil, methotrexate, pemetrexed, pralatrexate, trimetrexate and lamotrigine - and not one dihydropteroate synthase inhibitor.