Prontosil

Prontosil

Clinical data
Routes of administration	Oral
Identifiers
IUPAC name 4-[(2,4-diaminophenyl)azo]benzenesulfonamide
CAS Number	103-12-8
PubChem CID	66895
CompTox Dashboard (EPA)	DTXSID60145608
ECHA InfoCard	100.002.802
Chemical and physical data
Formula	C12H13N5O2S
Molar mass	291.33 g/mol g·mol−1

Prontosil, the first commercially available antibacterial antibiotic (with a relatively broad effect against Gram-positive cocci but not against enterobacteria), was developed by a research team at the Bayer Laboratories of the IG Farben conglomerate in Germany. The discovery and development of this first sulfonamide drug opened a new era in medicine.

History

Sulfonamidochrysoidine (KI-730), first synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch, was tested and found effective against some important bacterial infections in mice by Gerhard Domagk, who subsequently received the 1939 Nobel Prize in Medicine. Prontosil was the result of five years of research and testing involving thousands of compounds related to azo dyes. Leonard Colebrook introduced it as a cure for puerperal fever.

The crucial test result (in a murine model of Streptococcus pyogenes systemic infection) that preliminarily established the antibacterial efficacy of prontosil in mice dates from late December 1931. The readily water-soluble sodium salt of sulfonamidochrysoidine, which gives a burgundy red solution and was trademarked Prontosil Solubile, was clinically investigated between 1932 and 1934, first at the nearby hospital at Wuppertal-Elberfeld headed by Philipp Klee, and then at the Düsseldorf university hospital. The results were published in a series of articles in the February 15, 1935 issue of Germany's then pre-eminent medical scientific journal, Deutsche Medizinische Wochenschrift, and were initially received with some skepticism by a medical community bent on vaccination and crude immunotherapy.

As impressive clinical successes with Prontosil started to be reported from all over Europe, and especially after the widely published treatment of Franklin Delano Roosevelt, Jr. (a son of U.S. president Franklin D. Roosevelt), acceptance was quick and dozens of medicinal chemistry teams set out to improve on Prontosil.

Eclipse and legacy

Jacques and Thérèse Trefouel and their team at the French Pasteur Institute found in 1936 that prontosil is metabolized to sulfanilamide (para-aminophenylsulfonamide), a much simpler, colorless molecule, redefining Prontosil as a prodrug. Prontylin became the first oral version of sulfanilamide by Bayer.

Sulfanilamide was cheap to produce and was already off-patent when its antibiotic properties were first established. Its synthesis had been first reported by Paul Gelmo, a chemistry student working at the University of Vienna in his 1909 thesis, but he had not realized its medical potential. Since the sulfanilamide moiety was also easy to link into other molecules, chemists soon gave rise to hundreds of second-generation sulfonamide drugs. As a result, Prontosil failed to make the profits in the marketplace hoped for by Bayer. Although quickly eclipsed by these newer "sulfa drugs" and, in the mid-1940s and through the 1950s by penicillin and other antibiotics that proved more effective against more types of bacteria, Prontosil remained on the market until the 1960s. Prontosil's discovery ushered in the era of antibiotics and had a profound impact on pharmaceutical research, drug laws, and medical history.

Sulfonamide-trimethoprim combinations (Co-trimoxazole) are still used extensively for opportunistic infections in patients with AIDS, urinary infections and burn therapy. However, many other uses of sulfa drugs have been largely replaced by beta-lactam antibiotics.