Dihydrofolate Reductase Inhibitors

Abstract

While exploring structural variations of anilinopyrimidines with antimalarial activity, a group at Imperial Chemical Industries found that certain biguanides synthesised as ring-opened analogues possessed good activity against Plasmodium gallinaceum infections in chicks (Curd et al. 1945). Later, a group at Burroughs Wellcome who were testing various types of pyrimidines as inhibitors of nucleic acid synthesis pointed out a formal structural analogy between the most active of the biguanides, proguanil (chlorguanide), and a 2,4-diamino-5-aryloxypyrimidine which was a folic acid antagonist (Falco et al 1949). Soon after this, it was discovered that proguanil is cyclised metabolically to a dihydrotriazine, an active metabolite which is a folic acid antagonist (Carrington et al. 1951). Eventually, it was shown that the diaminopyrimidine, pyrimethamine, and the dihydrotriazine, cycloguanil, share a common locus of action — the powerful, selective inhibition of the activity of malarial dihydrofolate reductase (Ferone et al. 1969). Thus, one compound which was inadvertently synthesised as a prodrug and another which derived from a programme of synthesis of untargeted antimetabolites, together stand as prime examples of chemotherapeutic exploitation of species differences of isofunctional enzymes. These drugs have experienced 3 decades of widescale use for the prophylaxis and suppression of human malaria.