The sulfonamide-diaminopyrimidine story.
This paper is devoted to chemotherapy in the sense that Paul Ehrlich (Nobel Prize winner in 1908) coined the word: to describe the cure of infectious diseases by chemical agents without injury to the organism infected. This approach, essentially that of selective toxicity, is applicable to the investigations performed by Gerhard Domagk (Nobel Prize winner in 1939), which resulted in the development of Prontosil rubrum. This agent was active in vivo but not in vitro. Tréfouël supposed that the in vivo action was due to a metabolite of the drug (sulfanilamide), a hypothesis later proved by Fuller in 1937. Sulfanilamide was a simple agent, easy to manufacture and free of patent rights. Thus, more than 5400 derivatives were synthesized and studied in the decades that followed. Research on the side-effects of sulfonamides resulted in the development of diuretics and antidiabetogenic agents. The resurgence of interest in sulfonamides in following years has been associated with the development of diaminopyrimidines by Hitchings (Nobel Prize winner in 1988). It soon became evident that combinations of these drugs produced potent synergistic effects. Trimethoprim, a potent antibacterial agent of this series, was selected for combining with sulfonamides such as sulfadiazine. This line is still continued and even recently new diaminopyrimidine derivatives such as aditoprim and baquiloprim have been synthesized having superior properties in farm animal species. Thus, even nowadays the principles of Ehrlich continue to have a major impact on the development of new veterinary drugs.