Sulfonamides: Structure-Activity Relationships and Mechanism of Action

Abstract

The discovery of the antibacterial activity of prontosil (1) in the early 1930 s (Domagk 1935, 1957), the first effective chemotherapeutic agent to be employed for the systemic treatment of bacterial infection in humans (Foerster 1933), was the beginning of the present era of chemotherapy. The history of the development of sulfonamides as a major class of chemotherapeutic agents is one of the most fascinating chapters in drug research, highlighting the roles of skilful planning and serendipity. The synthesis of prontosil (1) was a carry-over of the interest generated in dyes in general as possible antimicrobials as a result ofE hrlich’s studies on the relationship between selective staining by dyes and their antiprotozoal activity, and in the sulfonamide group as contributory to fastness for acid wool dyes as a result of the work of Horlein, Dressel and Kethe of I.G. Farbenindustrie (see Mietzsch 1938), which led Mietzsch and Klarer (1935) to synthesize a group of azo dyes containing a sulfonamide group, which included prontosil. The lack of correlation between in vitro and in vivo antibacterial tests prompted Domagk (1935) to resort to in vivo testing, a very fortunate decision, since otherwise the fate of sulfonamides might have been different. In fact, similar dyes had been synthesized almost a decade earlier, such as p-sulfonamidobenzeneazodihydrocupreine (Heidelberger and Jacobs 1919), but tested in vitro, and thus understandably showing rather poor activity.