Sulfonamide (medicine)

Sulfonamides (more precisely sulfanilamides) are a group of synthetic chemical compounds with antimicrobial activity. Some representatives are therefore used as antibiotics. Their effect is based on the fact that they prevent bacteria from producing folic acid, which is necessary for the production of nucleotides, the basic building blocks of genetic material. Bacteria are thus not killed directly, but prevented from reproducing because they cannot copy their genetic information. Structurally, sulfonamides are derivatives of 4-aminobenzenesulfonamide; thus, they belong to the large group of sulfonamides characterized by the group -SO2NHR-. From the beginnings of the chemical-synthetic production of antimicrobial substances originates the term chemotherapeutic agent which is also still used for such active agents.

Substances structurally related to the sulfonamides are the sulfonylureas, which are used as oral antidiabetics, and the thiazide diuretics.

The action of sulfonamides as antimicrobial agents for the treatment of infectious diseases is based on the fact that they act as antimetabolites of p-aminobenzoic acid (PABA). They competitively inhibit the dihydropteroate synthase of the metabolic pathway of folic acid synthesis in bacteria, which catalyzes dihydropteroic acid formation. Eukaryotic (and thus also human) cells are not affected by this, as they do not produce folic acid. The effectiveness is also based on the structural similarity of sulfonamides with carboxylic acid amides, whereby their carbonyl group is replaced by a sulfonyl group; they are thus analogues of amides. Typical representatives are sulfamethoxazole, the longer-acting sulfadoxine, sulfacarbamide with a shorter duration of action, or sulfasalazine, which is not absorbed in the intestine. Sulfanilic acid itself has no appreciable effect against bacteria as it can hardly penetrate the membrane of the microorganisms due to its high polarity.

Manufacture

Different syntheses have been developed for the production of sulfonamides. Decisive for the chosen type of synthesis is the availability of the starting chemicals and a simple and trouble-free course of the intermediate steps. Electrochemical synthesis concepts open up reaction pathways, some of which allow direct introduction of the sulfonamide group under less drastic conditions.

Two possible syntheses for sulfapyridine are shown below as examples for the preparation of sulfonamides.

• Condensation of p-acetamino-benzene sulfochloride with an amine followed by hydrolysis of the acetyl group:

or as a second option:

• Condensation of p-nitrobenzenesulfonic acid chloride with an amine followed by reduction of the nitro group:

History

Development of synthetic antibiotics

With the scientific exploration and synthesis of organic compounds in the 19th century, the search for compounds with antibacterial properties also began. Paul Ehrlich was one of the first chemists to systematically investigate chemical compounds for their effect on bacteria. Ehrlich's work focused on azo dyes and similar compounds. After investigations with the azo dye trypan red and the arsenic-containing compound atoxyl, he suspected that structures with azo groups (-N=N-) as well as arsenic-organic compounds (-As=As-) were particularly suitable. Many new arsenic-containing compounds were therefore synthesized and tested in his laboratory.

For Salvarsan, developed in his laboratory in 1909, Ehrlich, together with the Japanese bacteriologist Sahachiro Hata, was able to demonstrate antibacterial activity against spirochetes and trypanosomes by 1910. With Salvarsan, a causal treatment and cure of syphilis with acceptable toxic side effects was possible for the first time. Salvarsan, developed in Germany, was patented and became known as one of the first fully synthetic drugs. The patent was confiscated by the USA during the First World War and the compound continued to be used under the name arsphenamine.

As early as 1908, Paul Gelmo had developed sulfanilamide, the first member of the sulfonamide group of substances. Heinrich Hörlein, who had already used sulfonamides with an azo structure (-N=N-) as textile dyes, was the driving force behind a research program at I. G. Farben for the systematic development of antibacterially active compounds from the group of dyes derived from coal tar chemistry, modeled on Ehrlich's Salvarsan.

In 1932, chemists Fritz Mietzsch and Josef Klarer synthesized a sulfonamide within this program that later became known under the brand name Prontosil. Its antibacterial effect was discovered shortly afterwards (in December 1932) by the physician Gerhard Domagk, who was researching the medicinal effect of azo dyes for I.G. Farben at Bayer's main plant in Wuppertal (Elberfeld) and was working closely with the chemists in his laboratory for experimental pathology in Elberfeld. Outside the living organism (in vitro), the initially synthesized KL 695 proved largely ineffective against streptococci, but it was effective in vivo in mice (KL 695 did not later go into clinical trials). The same was true for the variant Kl 730 synthesized and tested shortly thereafter, later named Streptozon and eventually Prontosil. In particular, the demonstration of the effect in animal models was the achievement of Domagk, who also successfully treated his four-year-old daughter, who had contracted sepsis, with the new drug in December 1933. The development was initially kept as secret as possible, but a patent was applied for as late as Christmas 1932 (not published until January 1935).

It was not until February 1935 that Domagk published his investigations into the medicinal efficacy of Prontosil and thus for the first time a description of the chemotherapeutic effect of sulfonamides. In 1939 Domagk was awarded the Nobel Prize for his work, but he was not allowed to accept it because of the laws during the National Socialist era. One reason for the delay in development was the opposition of the National Socialists, who came to power in 1933, to animal experiments.

The mechanism of action of prontosil was elucidated in 1935 by Jacques Tréfouël, Thérèse Tréfouël, Federico Nitti and Daniel Bovet in the laboratory of Ernest Fourneau: prontosil is first metabolized in the organism to the pharmacologically active form, sulfanilamide, which explains its ineffectiveness in vitro. Later there was a dispute as to whether Bayer scientists had also recognized the importance of the sulfanilamide component for the antibacterial effect. Bovet was of the opinion that they only came to this conclusion through the work of French scientists from the Pasteur Institute, as they believed in a connection between dye properties and antibacterial action. It was not until 1936 that testing began in bacteriological laboratories, clinical trials at IG Farben did not begin until March 1936, and later in 1936 it was marketed as Prontosil Album (album for colorless). In 1970, the British bacteriologist Ronald Hare, on the other hand, argued that Bayer's scientists had already known this, but were looking for a component that could be patented.

With the sulfonamides, the first broad-spectrum antibiotics were available that were used successfully in medicine. It was not until later in the Second World War, from 1940, that penicillin was also introduced into medical therapy by Florey and Dunn.

By the end of the 1930s, over 1000 sulfonamide compounds had been synthesized. However, only a few of them are pharmacologically active. All core-substituted derivatives of sulfanilamide tested so far are completely ineffective. Particularly effective, however, are compounds that have the structure:

contain.

The sulfonamides (year of introduction in parentheses) sulfapyridine (1938), sulfathiazole (1940), sulfaguanidine (1940), sulfadiazine (synonym: sulfapyrimidine, 1941), phthalylsulfathiazole (1942) and mono- and dimethyl derivatives of sulfathiazine (1943) were widely used.

The first drug with a sulfonamide active ingredient was Prontosil (sulfamidochrysoidine). Apart from Prontosil, most sulfonamides are active both in vitro and in vivo. The antibacterial mechanism of action of sulfonamides as antimetabolites was elucidated by Donald D. Woods and Paul Fildes in 1940.

In the course of the widespread use of sulphonamides in antimicrobial therapy, further effects were discovered with some of their representatives, which justified the development of further classes of active substances. In the 1940s, for example, the discovery of the diuretic effect of the sulfonamide sulfanilamide in particular led to the development of the new group of thiazide diuretics. The preparation Haflutan (6-chloro-benzene-1,3-disulfonamide), which stimulates urinary flow (reflex polyuria), also became known. Because of its blood sugar-lowering effect, the sulfonamide carbutamide was launched in 1956 as the first representative of the "sulfonylureas" used in antidiabetic therapy.

Penicillin and the various other compounds of this type have now largely replaced sulfonamides in medical use, as they are safer at lower doses. Among the few sulfonamides still used in the field of medicine for humans in modern times are the compounds sulfamethoxazole, silver sulfadiazine and sulfamerazine. In veterinary medicine, however, especially for the treatment of diseases caused by parasite infestation, combination preparations with sulfonamides are still frequently used.

Experiments at the time of National Socialism

During the National Socialist era, medical experiments on concentration camp inmates took place in the Ravensbrück concentration camp and Dachau concentration camp. The background was that Reinhard Heydrich died of sepsis while under the supervision of Himmler's personal physician Karl Gebhardt. Hitler's personal physician Morell had criticized that Heydrich might have survived if the sulfonamide Ultraseptyl had been used. However, other sulfonamides were administered to Heydrich, Gebhardt got into trouble and arranged the experiments. Concentration camp prisoners were inflicted with injuries and wounds were infected in order to achieve sepsis and to be able to test the mode of action of various sulfonamides. Gebhardt was sentenced to death for these experiments, among others, at the Nuremberg Doctors' Trial.