Sulfapyridin

DaMocles project by Silvia Nikova, Jordi Pfeifer Serrahima and André Zimmermann

Sulfapyridine (IUPAC-Name: 4-amino-N-pyridin-2-ylbenenesulfonamide) belongs to one of the first generation of sulphonamide antibiotics. It was used to treat infections like pneumonia or lgA disease.[17] Structure: History:

Sulfapyridine was discovered in 1937 by Lionel N H2N Whitby, a british scientist. The company May O & Baker Ldt. Lionel Whitby worked for, used sulfapyridine as antibiotic to cure bacterial S NH pneumonia and reached fast fame by curing O the British Prime Minister Winston Churchill. During World War II the drug was widespread, Fig.1. Sulfapyridine structure but soon after it was replaced by other sulfonamides. Some of them have been tested Sulfapyridine is a synthetic derivate of para- experimentally on concentration camp aminobenzoic-sulfonamide and is constructed inmates.[27] out of a benzene ring having an amino and a sulfonamide group. Synthesis:

For the synthesis of sulfapyridine two Properties: synthetic routes are common, which can be selected depending on the availability of the The para-position of the two side chains is starting chemicals. First, 2-aminopyridine important for antimicrobial activity. Through must be synthesized in both variants. different substitution at the nitrogen of the sulfonamide arise various derivates with different solubility, protein binding, tissue distribution, and elimination rate of metabolism. Sulfapyridine forms white to Fig.2. Synthesis of 2-aminopyridine yellow-white crystals, which dissolve in sugar This is done by heating pyridine with sodium water better than in water alone. The pH of a amide. A nucleophilic substitution is possible, [17] sulfapyridine-solution in water is neutral. because a heteroaromatic system has a lower electron density than a homoaromatic system Chemical data:[16][5] (Chichibabin reaction). The nucleophilic Molecular mass: 249,29 g/mol sodium-amide attacks the pyridine in ortho- position, because it is directed by the nitrogen CAS-number: 144-83-2 atom. The resulting anion is hydrolyzed to obtain the reactant 2-aminopyridine for Melting point: 192°C further synthesis. pKa: 8,43

LD50(orally in rats): 15800 mg/kg

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synthetase gets blocked, Tetrahydrofolic acid (THF), the “active” form of Folic acid cannot

be built. THF is used by the metabolism of all living organism for methyl group- or formyl group-donations.[18] This process is especially important for the synthesis of purines, pyrimidines and amino acid metabolism. For

example, the amino acids Glycine, Serine[21] and Methionine[19] are produced with the usage of THF. Furthermore, it has an

important role in the biosynthesis of dTMP, [20] which is produced from dUMP and has a major role in the repair of DNA.[25] The Fig.3. Synthesis of Sulfapyridine outcome of this is, that THF is fundamental for In the first synthesis step the p- the DNA-replication. If it is inhibited however, acetamidobenzenesulfochloride reacts with 2- the replication and growth of bacteria is aminopyridine under condensation of blocked,[24] which does not kill them directly, hydrogen chloride. The acetyl-group of the but the bacteria can now be fought much intermediate is hydrolyzed to obtain easier by the immune system.[13] Therefore, sulfapyridine. sulfonamides are also called folic acid antagonists.[11] They are however, for The second pathway is close to the previous mammalian cells, which include humans and synthesis, with a condensation of hydrogen animal cells, not dangerous, because folic acid chloride. This time the reactants are p- is absorbed through nutrition and therefore nitrobenzene sulfonylchloride and 2- an inhibition of the folic acid metabolism aminopyridine. In the second step, the nitro- would not affect us, as we take it directly from group of the intermediate product is reduced our food and can convert it to the needed by hydrogenation, whereby water and THF-form.[4] However, it can have some sulfapyridine arises.[27] serious side effects, which will be referred to

in the section significance.

Effect and usage: [28] Sulfonamides, also called sulfa drugs , operate antibacterial, bacteriostatic and antiparasitic against protozoen.[12] Their antimicrobial effect is caused by their special mechanism of action, which all sulfonamides have in common: They have a similar structure such as 4-Aminobenzoic acid (PABA)[24], which is used by the dihydropteoin acid-synthetase to form Dihydropterion acid, and can therefore work as a competitive inhibitor for this enzyme.[14] Competitive inhibitors can, due to their similar composition, bind to the catalytic domain of the enzyme, but will not be converted to a product and therefore will Fig.4. Synthesis of folic acid block the enzyme. If Dihydropteoinacid-

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The usage of sulfapyridine against infections is Significance: mostly discontinued due to the huge amount of side effects. However, there are some As mention before, sulfapyridine has serious exceptions like linear IgA dermatosis side effects so it is no longer prescribed for (autoimmune disease)[27], Dermatitis treatment of infections in humans. herpetiformis Duhring (bubble-forming autoimmune dermatosis)[3] and bullous In many cases, patients who were given pemphigoid (autoimmune disease)[2], where sulfapyridine suffered from damage of the sulfapyridine is still used. It also shows, that liver parenchyma, stomach ache, strong sulfapyridine can be taken as an unplanned icterus, vomiting, swelling of the liver and alternate treatment for Pyoderma tyrosine- and leucine crystals in the urine. It gangrenosum (autoimmune disease) and can be assumed that not an overdosing, but Subcorneal pustular dermatitis (rare skin rather individual hypersensitivity/Intolerance condition).[7] But its usage is very dependent or hypersensitivity of organs causes the side [1] of the patient’s reaction to Dapson, another effects mentioned. sulfonamide, which is normally used for these diseases and more effective than As with other sulfonamides, there is a sulfapyridine. If the patient shows intolerance significant risk of agranulocytosis very low to dapson, sulfapyridine needs to be concentration of granulocytes (a major class prescribed.[15] Normally sulfapyrdine will be of white blood cells), which is the main reason taken orally in tablet form[8] and work after a for its decline in use. period of latency of 4-6 hours.[14] Its water solubility is very pH dependent, thus

there is a risk of crystallization within In general Sulfonamides are not often used the bladder or urethra, which may lead to pain [27] nowadays due to the development of or blockage. bacterial resistance, because of their long usage. For this reason, sulfonamides are often Relations: used with other medicaments, which block Sulfapyridine is part of above-mentioned the folic acid metabolism in another point, sulfonamides. The para-position of the such as the Dihydrofolate reductasis-inhibitor sulfonamide side chains is significant for the Trimethopromin.[10] Sulfonamides are often antibacterial effect. With a substitution on used for rodents, because they do not tolerate nitrogen of the sulfonamide group many antibiotics.[24] They are typically prescribed for sulfonamides with different solubility, protein infections in the urinary passage[4], binding, metabolism and elimination rate are enderoanastomosis, infections caused by formed.[30] protozoen[12] or for autoimmune diseases, Two of the frequently-used sulfonamides are where, as I mentioned above, sulfapyridine is described below. still used frequently. The few nowadays used sulfonamides are Sulfamethoxazol,

Silbersufladiazin and Sulfamerazin.[4] In

Germany only sulfadiazine is allowed to be used alone to treat acute and recurring toxoplasmosis, which is an infection, often [26] occurring in cats. Fig.5. Basic structure of sulfonamide

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Sulfasalazine Sulfamethoxazole

Fig.6. Sulfasalazine structure Fig. 8. Sulfamethoxazole structure

Sulfasalazine consists of one molecule of 5- Sulfamethoxazole is an antibiotic used for aminosalicylic acid bacterial infections such as urinary tract (5-ASA, mesalamine) coupled by an azo bond infections, bronchitis, and prostatitis and is to one molecule of sulfapyridine. effective against both gram negative and Sulfasalazine is used for the treatment positive bacteria such as Listeria of inflammatory bowel disease, monocytogenes and E. coli. Sulfamethoxazole including ulcerative colitis and Crohn's is normally given in combination with disease. It is also indicated for use when Trimethoprim as an antibiotic Cotrimoxazole. treating rheumatoid arthritis and used for Sulfamethoxazole inhibits bacterial synthesis other types of inflammatory arthritis. of dihydrofolic acid by competing with para- aminobenzoic acid (PABA) for binding to It is a prodrug, meaning that it is not active in dihydrofolate synthetase, an intermediate of its ingested form. It is broken down by tetrahydrofolic acid (THF) synthesis, which is bacterial enzyme azoreductase in required for DNA synthetis.[6] the colon into its two components, 5- aminosalicylic acid, and sulfapyridine. But only 5-ASA has a therapeutic benefit.[9] Reference list: The sulfapyridine moiety is inactive and causes [1]Greiner K., Toxische Leberschädigung bei der most of the allergic and intolerant effects of Behandlung mit Sulfapyridin, Klinische Wochenschrift, sulfasalazine. Therefore, 5-ASA and other January 1941, Volume 20, Issue 4, pp 97-99 derivatives of 5-ASA are now usually preferred [2]http://archderm.jamanetwork.com/article.aspx?articleid=53 and given alone (as mesalazine).[23] 7171 (last access 02.03.2016) 5-ASA mechanism of action on the one hand, [3]http://emedicine.medscape.com/article/1062640-treatment (last access 02.03.2016) involves the inhibition of the cyclooxygenase and lipoxygenase activity, and thus decrease [4]http://flexikon.doccheck.com/de/Sulfonamid-Antibiotikum (last access 02.03.2016) of synthesis of prostaglandins, leukotrienes [5]http://www.drugbank.ca/drugs/DB00891 (last access and free radicals, on the other hand, the 02.03.2016) suppression of the immune response in the [6]http://www.drugbank.ca/drugs/DB01015 (last access [29] intestinal mucosa. 02.03.2016)

[7]http://www.drugs.com/cons/sulfapyridine.html (last access 02.03.2016) [8]http://www.mayoclinic.org/drugs- supplements/sulfapyridine-oral-route/description/drg- 20066133 (last access 02.03.2016)

[9]http://www.medicinenet.com/sulfasalazine/article.htm (last access 02.03.2016) Fig.7. 5-ASA mechanism of action [10]http://www.onmeda.de/Wirkstoffgruppe/Sulfonamide+und +Trimethoprim.html (last access 02.03.2016)

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[11]http://www.pharmawiki.ch/wiki/index.php?wiki=Fols%C3% A4ure-Antagonisten (last access 02.03.2016)

[12]http://www.pharmawiki.ch/wiki/index.php?wiki=Sulfonami de (last access 02.03.2016)

[13]http://www.vetpharm.uzh.ch/reloader.htm?wir/00000005/ 7681_02.htm?wir/00000005/7681_00.htm (last access 02.03.2016)

[14]http://www.vetpharm.uzh.ch/reloader.htm?wir/00000014/ 4832_02.htm?wir/00000014/4832_00.htm (last access 02.03.2016)

[15]https://books.google.de/books?id=N_D5CQAAQBAJ&pg=PA 645&lpg=PA645&dq=dapson+more+effective+sulfapyridine&so urce=bl&ots=e0mvVy0JCq&sig=kxF30BKXyIJLw3Obm9Z6_nsm_z c&hl=de&sa=X&ved=0ahUKEwi- y4rpldfKAhVG5A4KHSYJCGkQ6AEIHzAA#v=onepage&q=dapson %20more%20effective%20sulfapyridine&f=false (last access 02.03.2016)

[16]https://pubchem.ncbi.nlm.nih.gov/ (last access 02.03.2016)

[17]https://pubchem.ncbi.nlm.nih.gov/compound/sulfapyridine #section=Top (last access 02.03.2016)

[18]https://de.wikibooks.org/wiki/Biochemie_und_Pathobioche mie:_Folat-Stoffwechsel (last access 02.03.2016)

[19]https://de.wikibooks.org/wiki/Biochemie_und_Pathobioche mie:_Methionin-Stoffwechsel (last access 02.03.2016)

[20]https://de.wikibooks.org/wiki/Biochemie_und_Pathobioche mie:_Pyrimidin- Stoffwechsel#Biosynthese_von_dTMP_aus_dUMP (last access 02.03.2016)

[21]https://de.wikibooks.org/wiki/Biochemie_und_Pathobioche mie:_Threonin-,_Glycin-_und_Serin- Stoffwechsel#Biosynthese_von_Glycin_aus_L-Serin_und_Abbau (last access 02.03.2016)

[22]https://de.wikibooks.org/wiki/Biochemie_und_Pathobioche mie:_Threonin-,_Glycin-_und_Serin- Stoffwechsel#Biosynthese_von_Glycin_aus_L-Serin_und_Abbau (last access 02.03.2016)

[23]https://de.wikipedia.org/wiki/Sulfasalazin (last access 02.03.2016)

[24]https://de.wikipedia.org/wiki/Sulfonamide (last access 02.03.2016)

[25]https://de.wikipedia.org/wiki/Thymidylat-Synthase (last access 02.03.2016)

[26]https://de.wikipedia.org/wiki/Toxoplasmose (last access 02.03.2016)

[27]https://en.wikipedia.org/wiki/Sulfapyridine (last access 02.03.2016)

[28]https://en.wikipedia.org/wiki/Sulfonamide_%28medicine% 29 (last access 02.03.2016)

[29]Lodowska J. et al., The effect of sulfasalazine and 5- aminosalicylic acid on the secretion of interleukin 8 by human colon myofibroblasts, Acta Pol Pharm. 2015 Sep-Oct; 72(5):917- 21

[30]McEvoy GK, AHFS Drug Information 1992, American Society of Hospital Pharmacists Inc, Bethesda (USA); 2363 pp, 1992

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