DEVELOPMENT OF THE DIAMINOPYRIMIDINES

The history of the biochemical studies and chemical synthesis leading to our present selective inhibitors of dihydrofolate reductase is reviewed. Inhibitors are divided into the classical or folate-like inhibitors such as aminopterin and amethopterin and the ‘small molecule’ inhibitors such as trimethoprim. The biochemistry of the folate pathway is surveyed from the viewpoint of the chemo-therapist seeking to exploit biochemical differences between parasite and host. The selective inhibition of dihydrofolate reductase is documented and its implications for the design of drugs aimed at specific infectious diseases considered. The concept of synergism is reviewed with emphasis on the configuration of the folate pathways and the consequences for drug interaction. The present status of medically useful antifolates is summarized. © 1979 Oxford University Press.