Arsphenamine, also known asSalvarsan orcompound 606, is anantibioticdrug that was introduced at the beginning of the 1910s as the first effective treatment for the deadlyinfectious diseasessyphilis,relapsing fever, andAfrican trypanosomiasis.[2][3]Thisorganoarsenic compound was the first modernantimicrobial agent.[4]
Arsphenamine was first synthesized in 1907 inPaul Ehrlich's lab byAlfred Bertheim.[4] The antisyphilitic activity of this compound was discovered bySahachiro Hata in 1909, during a survey of hundreds of newly synthesized organicarsenical compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered that would have anti-microbial activity but not kill the human patient. Ehrlich's team began their search for such a "magic bullet" among chemical derivatives of the dangerously toxic drugatoxyl.
Arsphenamine was used to treat the diseasesyphilis because it is toxic to thebacteriumTreponema pallidum, aspirochete that causes syphilis.[6]
Arsphenamine was originally called "606" because it was the sixth in the sixth group of compounds synthesized for testing; it was marketed byHoechst AG under thetrade name "Salvarsan" in 1910.[7][8] Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganicmercury compounds that had been used previously. It was distributed as a yellow, crystalline,hygroscopic powder that was highly unstable in air.[9] This significantly complicated administration, as the drug had to be dissolved in several hundred milliliters of distilled, sterile water with minimal exposure to air to produce a solution suitable for injection. Some of the side effects attributed to Salvarsan, including rashes, liver damage, and risks of life and limb, were thought to be caused by improper handling and administration.[10] This caused Ehrlich, who worked assiduously to standardize practices, to observe, "the step from the laboratory to the patient's bedside ... is extraordinarily arduous and fraught with danger."[7]
Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound,Neosalvarsan (neoarsphenamine), which was easier to prepare, and it became available in 1912. Less severe side-effects such as nausea and vomiting were still common. An additional problem was that both Salvarsan and Neosalvarsan had to be stored in sealed vials under anitrogen atmosphere to prevent oxidation. These arsenical compounds were supplanted as treatments for syphilis in the 1940s bypenicillin.[11]
After leaving Ehrlich's laboratory, Hata continued parallel investigation of the new medicines inJapan.[12]
Salvarsan has long been assumed to have an As=Asdouble bond, akin to the N=N linkage inazobenzene. However, in 2005, in an extensivemass spectrometric analysis, the arsenic–arsenic bonds in Salvarsan were shown to be single bonds rather than double bonds. Presumed to consist of RAs=AsR molecules, i.e. (RAs)2, Salvarsan was found to actually contain a mixture of cyclo-(RAs)3 and cyclo-(RAs)5 species, where R is the 3-amino-4-hydroxyphenylmoiety.[1][13] According to Nicholson,[1] these cyclic species slowly release an oxidised species, RAs(OH)2, that is likely responsible for Salvarsan's antisyphilis properties.[7]