View Full Version : Where It All started: Sulfa Drugs and a Brief History of Chemotherapy

31st May 08, 09:58 AM
Where It All started: Sulfa Drugs and a (very) Brief History of Chemotherapy

Before 1900 there were only 3 known chemical remedies that had specific curative properties: Mercury (for the treatment of syphilis (http://en.wikipedia.org/wiki/Syphilis)), ipecacuanha (http://en.wikipedia.org/wiki/Ipecacuanha)(for dysentery) and cinchona bark (http://en.wikipedia.org/wiki/Cinchona) (for malaria). In the last century, however, we’ve seen an explosion of chemicals used to remedy specific illnesses. This advancement can be traced all the way back to the pioneering work of Paul Ehrlich (http://en.wikipedia.org/wiki/Paul_Ehrlich) in the early 1900’s.

Even as a young student, Ehrlich was fascinated by the ability of certain dyes to stain specific tissues (gram negative/positive bacteria (http://en.wikipedia.org/wiki/Gram_negative) for example). He reasoned that the dyes stain by chemical reaction with specific elements common (http://en.wikipedia.org/wiki/Side-chain_theory) in certain tissues. Working with this idea later in life, he reasoned that he might find a chemical with a specific affinity for microorganisms and modify it to destroy it. Ehrlich’s first success was with the dye Trypan Red 1 (http://www.britannica.com/EBchecked/topic/607486/trypan-red), which was the first drug to show activity against trypanosomal infections in mice. Later in 1906, he deduced the true chemical structure of the chemical Atoxyl (http://en.wikipedia.org/wiki/Atoxyl), a slighty less toxic arsenic containing compound (when compared to arsenic). This led to the co-discovery (with Sahachiro Hata) of salvarsan (http://en.wikipedia.org/wiki/Salvarsan), which was found to be an effective treatment for syphilis and trypanosomiasis. He continued his researches to find these “magic bullets” until his death from a stroke in 1915. He was 61 at the time.

In 1935, based on Ehrlich’s work, a German pathologist named Gerhard Domagk (http://en.wikipedia.org/wiki/Gerhard_Domagk) found that a dye called prontosil (http://en.wikipedia.org/wiki/Prontosil) was effective against streptococcal infections. His research was proven further when his young daughter was infected from a pinprick and he gave her an oral dose of the dye. The dye saved her arm from amputation and probably her life too. On a side note, he was awarded the Nobel Prize for his research, but was unable to accept it until after the war due to German law at the time and was also arrested by the ungrateful gestapo. Prontosil later became the first antibacterial drug and the first widely available sulfa drug. In 1936, Ernest Fourneau showed that protosil breaks down into the chemical sulfanilamide and was the active ingredient in the drug.

Cheap and easy to produce, the sulfanilamide (http://en.wikipedia.org/wiki/Sulfanilamide) structure was the host of several thousand attempts to make even more effective drugs and gave birth to the class of chemicals known as sulfa drugs (http://en.wikipedia.org/wiki/Sulfa_drugs). Drugs such as Sulfapyridine (http://en.wikipedia.org/wiki/Sulfapyridine) (effective against pneumonia), Sulfacetamide (http://en.wikipedia.org/wiki/Sulfacetamide) (urinary tract infections) and Sulfathiazole (http://en.wikipedia.org/wiki/Sulfathiazole) saved thousands of lives and changed medicine forever. Though widely displaced with the discovery of penicillin, they still find a wide variety of uses, including against antibiotic resistant bacteria, urinary tract infections and acne.

Notice (No, not my handwriting) that sulfanilamide structure is only changed by adding a different functional group to the SO2NH2 group. It was found that the most successful chemicals were usually ones that replaced the hydrogen atom with what is known as a heterocyclic ring.


The drugs work by inhibiting the action of another chemical: p-aminobenzoic acid. They are structurally similar and the two compete with each other in some metabolic processes. The bond lengths are also very similar in size, almost a perfect match.

On a different subject, Ehrlich is also famous for his side chain theory, an idea which was fully realized with the development of monoclonal antibodies. I felt I had to mention it here.

31st May 08, 05:46 PM
Did mercury actually work in the treatment of syphilis? I'd always assumed it was next to useless.

31st May 08, 06:09 PM
yes, in roman times they would heat it in a box and vaporize it while the patient would sit above it. It was probably quite painful in that molten metal sort of way. Undoubtedly, it was the worst, most ineffective way to deliver Hg to the spirochetes to kill them. Much like hiccup remedies, it was probably made more for other people's amusement rather than treatment of the disease.

this is where the old quip: In night with venus leads to a lifetime on mercury (or something like that) comes from.