Prontosil

Prontosil

Clinical data
Routes of administration	Oral
Identifiers
IUPAC name 4-[(2,4-diaminophenyl)azo]benzenesulfonamide
CAS Number	103-12-8 N
PubChem CID	66895
ChemSpider	16736190 Y
ChEMBL	ChEMBL488279 N
CompTox Dashboard (EPA)	DTXSID60145608
ECHA InfoCard	100.002.802
Chemical and physical data
Formula	C12H13N5O2S
Molar mass	291.33 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES NS(=O)(=O)c2ccc(/N=N/c1ccc(N)cc1N)cc2
InChI InChI=1S/C12H13N5O2S/c13-8-1-6-12(11(14)7-8)17-16-9-2-4-10(5-3-9)20(15,18)19/h1-7H,13-14H2,(H2,15,18,19) Y Key:ABBQGOCHXSPKHJ-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Prontosil, the first commercially available antibacterial antibiotic (with a relatively broad effect against Gram-positive cocci but not against enterobacteria), was developed in the 1930s 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 was first synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch as part of a research program designed to find dyes that might act as antibacterial drugs in the body. The molecule was tested and in the late autumn of 1932 was 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 testing involving thousands of compounds related to azo dyes.

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. IG Farben filed a German patent application concerning its medical utility on December 25, 1932. The synthesis of the compound had been first reported by Paul Gelmo, a chemistry student working at the University of Vienna in his 1909 thesis, although he had not realized its medical potential.

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.

Then Leonard Colebrook introduced it as a cure for puerperal fever. 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. (Eleanor Bliss and Perrin Long from Johns Hopkins introduced the drug to the United States.)

Eclipse and legacy

In late 1935, working at the Pasteur Institute in Paris in the laboratory of Ernest Fourneau, Jacques and Thérèse Tréfouël, Daniel Bovet and Federico Nitti discovered that Prontosil is metabolized to sulfanilamide (para-aminobenzenesulfonamide), a much simpler, colorless molecule, redefining Prontosil as a prodrug. Prontylin became the first oral version of sulfanilamide by Bayer, which had actually obtained a German patent on sulfanilamide as early as 1909, without realizing its medical potential at this time.

It has been argued that IG Farben might have made its breakthrough discovery with sulfanilamide in 1932 but, recognizing that it would not be patentable as an antibiotic, had spent the next three years developing Prontosil as new, and therefore more easily patentable, compound. However Daniel Bovet, Nobel Prize of medicine and one of the authors of the French discovery, wrote in 1988: "Today, we have the proof that the chemists of Elberfeld were unaware of the properties of sulfanilamide at the time of our discovery and that it was by our communication that they were informed. To be convinced about it, it is enough to attentively examine the monthly reports of work of Mietzsch and Klarer during years 1935-1936 and especially the Log Book of G. Domagk: the formula of sulphamide is consigned there - without comment - not before January 1936."

Sulfanilamide was cheap to produce and (due to the early date of its original composition of matter patent which made no reference to a medical use) was already off-patent when its antibiotic properties were first made public. 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.