Prontosil: Structure, Discovery, and Uses in Biology

Prontosil is a sulfonamide-based antibacterial medication. It does have a wide antibacterial activity against gram-positive cocci but not enterobacteria. It was among the first antimicrobial medications, and it was extensively used throughout the mid-20th century, but it has been rarely used due to the availability of better alternatives. The invention and development of this first sulfonamide medication ushered in a new age in medicine, as it significantly increased the effectiveness of antimicrobial chemotherapy at a time when numerous doctors dismissed its yet mostly untapped potential. 

Disinfectant cleaners and antiseptic topical wound care were common at the time, however, there have been very few antimicrobial drugs that could be safely used within the living bodies. Antibiotic drugs extracted from microbes, on which we relied and would be relying heavily, did not exist at the time. Prontosil was identified in 1932 by a research group at the IG Farben conglomerate's Bayer Laboratories in Germany.

Prontosil Structure

[Image will be uploaded soon]

Names

Sulfamido Chrysoidine, aseptil rojo, streptocide, prontosil flavum, prontosil rubrum, rubiazol, and sulfamidochrysodine hydrochloride are some of the nonproprietary names, however, the capitalized name "Prontosil" is Bayer's trade name.

Because the drug predates the contemporary structure of drug naming, which assures that nonproprietary names are quite well recognized from the start of marketing, the population primarily knew it with its trade name, which was the source of a few of the nonproprietary names (similarly happened with "aspirin").

Prontosil History

Josef Klarer and Fritz Mietzsch of Bayer first synthesised this compound as part of a training programme to discover prontosil dye which could behave as antibacterial drugs in the body. Gerhard Domagk, who won the Nobel Prize in Medicine in 1939, screened the molecule and discovered it effective against certain essential bacterial infections in mice in late autumn of 1932. Prontosil was developed after five years of research involving thousands of azo dye-related compounds.

Late December 1931 saw the crucial analysis results (in a murine model of Streptococcus pyogenes systemic infection) which preliminarily formed Prontosil's antibacterial efficacy in mice. On December 25, 1932, IG Farben filed a German patent application for its medical utility. Paul Gelmo, a chemistry university student of Vienna, had first confirmed the compound's synthesis in his 1909 thesis since he had not realised its medical potential.

Between 1932 and 1934, the readily water-soluble sodium salt of sulfonamidochrysoidine, which yields a burgundy red solution and had been marketed Prontosil Solubile, was therapeutically researched, first at Philipp Klee's neighbouring hospital in Wuppertal-Elberfeld, and later at the Düsseldorf University Hospital. The results were confirmed and posted in a series of papers in the February 15, 1935 issue of Deutsche Medizinische Wochenschrift, Germany's then-preeminent medical research publication, and were first met with suspicion by a medical establishment fixated on vaccination and crude immunotherapy.

It was first introduced by Leonard Colebrook as a treatment for puerperal fever. Acceptance occurred rapidly as significant clinical achievements with Prontosil began to be documented from all across Europe, particularly after a highly publicized treatment of Franklin Delano Roosevelt, Jr. (son of US President Franklin D. Roosevelt) in 1936, and dozens of medicinal chemistry groups set out to enhance Prontosil.

Discovery of Prontosil

A drug's role, according to Domagk, would have been to communicate with the immune system, whether it's to strengthen it or to make the infection agent so vulnerable that the immune system might easily defeat it. He valued drug testing in biological systems so much that he was willing to keep functioning with a compound even after it failed to evaluate bacteria cultured in laboratory glassware. A few connected to azo prontosil dye were one of the hundreds of chemical compounds formulated by Mietzsch and Klarer for domagk prontosil to evaluate. 

They possessed the typical azo dye -N=N- coupling, although one of the hydrogens on nitrogen had been substituted by a sulfonamide group. The two scientists published a chemical (KL 695) in 1931 that, despite being inactive in vitro, was slightly active in streptococcus-infected laboratory mice. Chemists changed the structure of this molecule and generated KL 730, which had extraordinary antibacterial benefits on ill laboratory animals after several months and 35 compounds. Prontosil rubrum was the name given to it, and it was trademarked as Prontosil.

Domagk spent the following three years researching Prontosil's antibacterial capabilities. In 1935, he eventually published his first report on his findings. Prontosil had been used successfully in people for the previous three years to treat a variety of infections caused by both streptococcal and staphylococcal bacteria. Domagk's own six-year-old daughter, Hildegard, was one among the first patients, having developed a serious streptococcal infection from an unsterilized injection. She recovered, however, the medicine caused a persistent reddish tint of her skin.

Eclipse and Legacy

Dr. Ernest Fourneau, Jacques and Thérèse Tréfoul, Dr. Daniel Bovet, and Federico Nitti found that Prontosil is converted to sulfanilamide (para-aminobenzenesulfonamide), an even simpler, colourless compound, reclassifying Prontosil like a prodrug in late 1935 while researching at the Pasteur Institute in Paris in the laboratory. Bayer developed Prontalbin, the very first oral edition of sulfanilamide. Bayer would have acquired a German patent on sulfanilamide in 1909 but had not realised its medical potential at the period.

This has been suggested that IG Farben achieved its breakthrough discovery with sulfanilamide in 1932, however, devoted the very next 3 years to inventing Prontosil as just a new, and hence more readily patentable, molecule after realising that this would not be patented as an antibiotic. However, in 1988, Dr. Bovet, a Nobel Laureate in medicine and also one of the writers of the French research, authored: "Today, we have the proof that the scientists of Elberfeld remained unaware of the qualities of sulfanilamide at the moment of our invention and that they had been enlightened by our message. Towards being reassured of this, thoroughly consider Mietzsch and Klarer's monthly work findings for the years 1935–1936, particularly Gerhard Domagk's Log Book: the sulphamide formula is relegated there – without comment – not until January 1936."