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Sulfonamide functional group

Hydrochlorothiazide is a sulfonamide and a thiazide.

Furosemide is a sulfonamide, but not a thiazide.

Sulfamethoxazole is an antibacterial sulfonamide

Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides.^[1]^[2]

Allergies to sulfonamide are common,^[3] hence medications containing sulfonamides are prescribed carefully. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamides.

Because sulfonamides displace bilirubin from albumin, kernicterus (brain damage due to excess bilirubin) is an important potential side effect of sulfonamide use.

1 Function
- 1.1 Antimicrobial
- 1.2 Other uses
2 History
3 Preparation
4 List of sulfonamides
- 4.1 Child antibacterial drugs
- 4.2 Antimicrobials
- 4.3 Sulfonylureas (anti-diabetic agents)
- 4.4 Diuretics
- 4.5 Anticonvulsants
- 4.6 Dermatologicals
- 4.7 Antiretrovirals
- 4.8 Stimulant
- 4.9 Other
5 Side effects
6 See also
7 References
8 External links

Function

Antimicrobial

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS), an enzyme involved in folate synthesis. Sulfonamides are therefore bacteriostatic and inhibit growth and multiplication of bacteria, but do not kill them. Humans, in contrast to bacteria, acquire folate (vitamin B₉) through the diet.^[4]

Structural similarity between sulfonamide (left) and PABA (center) is the basis for the inhibitory activity of sulfa drugs on dihydrofolate (right) biosynthesis

Other uses

The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others), loop diuretics (including furosemide, bumetanide, and torsemide), acetazolamide, sulfonylureas (including glipizide, glyburide, among others), and some COX-2 inhibitors (e.g., celecoxib).

Sulfasalazine, in addition to its use as an antibiotic, is also used in the treatment of inflammatory bowel disease.

History

Sulfonamide drugs were the first antibiotics to be used systemically, and paved the way for the antibiotic revolution in medicine. The first sulfonamide, trade-named Prontosil, was a prodrug. Experiments with Prontosil began in 1932 in the laboratories of Bayer AG, at that time a component of the huge German chemical trust IG Farben. The Bayer team believed that coal-tar dyes which are able to bind preferentially to bacteria and parasites might be used to attack harmful organisms in the body. After years of fruitless trial-and-error work on hundreds of dyes, a team led by physician/researcher Gerhard Domagk^[5] (working under the general direction of Farben executive Heinrich Hörlein) finally found one that worked: a red dye synthesized by Bayer chemist Josef Klarer that had remarkable effects on stopping some bacterial infections in mice.^[6] The first official communication about the breakthrough discovery was not published until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz Mietzsch.

Prontosil, as Bayer named the new drug, was the first medicine ever discovered that could effectively treat a range of bacterial infections inside the body. It had a strong protective action against infections caused by streptococci, including blood infections, childbed fever, and erysipelas, and a lesser effect on infections caused by other cocci. However, it had no effect at all in the test tube, exerting its antibacterial action only in live animals. Later, it was discovered by Bovet,^[7] Federico Nitti and J. and Th. Jacques Tréfouël, a French research team led by Ernest Fourneau at the Pasteur Institute, that the drug was metabolized into two pieces inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide.^[8] The discovery helped establish the concept of "bioactivation" and dashed the German corporation's dreams of enormous profit; the active molecule sulfanilamide (or sulfa) had first been synthesized in 1906 and was widely used in the dye-making industry; its patent had since expired and the drug was available to anyone.^[9]

The result was a sulfa craze.^[10] For several years in the late 1930s, hundreds of manufacturers produced tens of thousands of tons of myriad forms of sulfa. This and nonexistent testing requirements led to the elixir sulfanilamide disaster in the fall of 1937, during which at least 100 people were poisoned with diethylene glycol. This led to the passage of the Federal Food, Drug, and Cosmetic Act in 1938 in the United States. As the first and only effective antibiotic available in the years before penicillin, sulfa drugs continued to thrive through the early years of World War II.^[11] They are credited with saving the lives of tens of thousands of patients, including Franklin Delano Roosevelt, Jr. (son of US President Franklin Delano Roosevelt) and Winston Churchill. Sulfa had a central role in preventing wound infections during the war. American soldiers were issued a first-aid kit containing sulfa pills and powder, and were told to sprinkle it on any open wound.

The sulfanilamide compound is more active in the protonated form. The drug has very low solubility and sometimes can crystallize in the kidneys, due to its first pK_a of around 10. This is a very painful experience, so patients are told to take the medication with copious amounts of water. Newer analogous compounds prevent this complication because they have a lower pK_a, around 5–6,^{[citation needed]} making them more likely to remain in a soluble form.

Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5,400 permutations by 1945), yielding improved formulations with greater effectiveness and less toxicity. Sulfa drugs are still widely used for conditions such as acne and urinary tract infections, and are receiving renewed interest for the treatment of infections caused by bacteria resistant to other antibiotics.

Preparation

Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. Certain sulfonamides (sulfadiazine or sulfamethoxazole) are sometimes mixed with the drug trimethoprim, which acts against dihydrofolate reductase. As of 2013, Republic of Ireland is the largest exporter worldwide of Sulfonamides, accounting for approximately 32% of total exports.^[12]

List of sulfonamides

Child antibacterial drugs

Pediazole^[13]

Antimicrobials

Short-acting^[14]

Sulfacetamide
Sulfadiazine
Sulfadimidine
Sulfafurazole
Sulfisomidine (aka sulfaisodimidine)

Intermediate-acting

Sulfadoxine
Sulfamethoxazole
Sulfamoxole
Sulfanitran

Long-acting

Sulfadimethoxine
Sulfamethoxypyridazine
Sulfametoxydiazine

Ultra long-acting

Sulfadoxine
Sulfametopyrazine

Sulfonylureas (anti-diabetic agents)

Acetohexamide
Carbutamide
Chlorpropamide
Glibenclamide (also known as glyburide)
Glibornuride
Gliclazide
Glyclopyramide
Glimepiride
Glipizide
Gliquidone
Glisoxepide
Tolazamide
Tolbutamide

Diuretics

Acetazolamide
Bumetanide
Chlorthalidone
Clopamide
Dorzolamide
Furosemide
Hydrochlorothiazide (HCT, HCTZ, HZT)
Indapamide
Mefruside
Metolazone
Xipamide

Anticonvulsants

Ethoxzolamide
Sultiame
Topiramate (a sulfamate, not a true sulfonamide)
Zonisamide

Dermatologicals

Mafenide

Antiretrovirals

Amprenavir (protease inhibitor)
Darunavir (protease inhibitor)
Delavirdine (non-nucleoside reverse transcriptase inhibitor)
Fosamprenavir (protease inhibitor)
Simeprevir (protease inhibitor)
Tipranavir (protease inhibitor)

Stimulant

Azabon

Other

Apricoxib (COX-2 inhibitor)
Bosentan (endothelin receptor antagonist)
Celecoxib (COX-2 inhibitor)
Dofetilide (class III antiarrhythmic)
Dronedarone (class III antiarrhythmic)
Ibutilide (class III antiarrhythmic)
Parecoxib (COX-2 inhibitor)
Probenecid (PBN)
Sotalol (beta blocker)
Sulfasalazine (SSZ)
Sumatriptan (SMT)
Tamsulosin (alpha blocker)
Udenafil (PDE5 inhibitor)

Side effects

Patient suffering from Stevens–Johnson syndrome

Sulfonamides have the potential to cause a variety of untoward reactions, including urinary tract disorders, haemopoietic disorders, porphyria, and hypersensitivity reactions. When used in large doses, they may cause a strong allergic reaction. Two of the most serious are Stevens–Johnson syndrome and toxic epidermal necrolysis (also known as Lyell syndrome).^[3]

Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%.^[15]

Hypersensitivity reactions are less common in nonantibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the nonantibiotic agents.^[16] A key component to the allergic response to sulfonamide antibiotics is the arylamine group at N4, found in sulfamethoxazole, sulfasalazine, sulfadiazine, and the anti-retrovirals amprenavir and fosamprenavir. Other sulfonamide drugs do not contain this arylamine group; available evidence suggests that patients who are allergic to arylamine sulfonamides do not cross-react to sulfonamides that lack the arylamine group, and may therefore safely take non-arylamine sulfonamides.^[17] It has therefore been argued that the terms 'sulfonamide allergy' or 'sulfa allergy' are misleading, and should be replaced by a reference to a specific drug (e.g. 'cotrimoxazole allergy').^[18]

Allergic urticaria on the skin induced by an antibiotic

Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class.

The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction.
The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response.

The nonantibiotic sulfonamides lack both of these structures.^[19]

The most common manifestations of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, fulminant hepatic necrosis, and acute pancreatitis, among others.^[20]

References

^ Henry RJ (1943). "The Mode of Action of Sulfonamides". Bacteriological reviews 7 (4): 175–262. PMC 440870. PMID 16350088.
^ "SULFONAMIDE CLASS ANTIBIOTICS". chemicalland21.com. Retrieved 17 January 2014.
^ ^a ^b "Sulfa Drugs Allergy -- Sulfa Bactrim Drug Allergies". allergies.about.com. Retrieved 17 January 2014.
^ M. Madigan, J. Martinko, D. Stahl, D. Clark, Brock Biology of Microorganisms (13th ed.), Pearson Education, 2012, p. 797 ISBN 9780321735515
^ Otten H (1986). "Domagk and the development of the sulphonamides". Journal of Antimicrobial Chemotherapy 17 (6): 689–696. doi:10.1093/jac/17.6.689. PMID 3525495.
^ Hager, Thomas (2006-09-01). "The Demon Under the Microscope: From Battlefield Hospitals to Nazi Labs, One Doctor's Heroic Search for the World's First Miracle Drug". ISBN 978-0-307-35228-6.
^ Cf. Daniel Bovet, Une chimie qui guérit : Histoire de la découverte des sulfamides, Paris, Payot, coll. « Médecine et sociétés », 1988 (ISBN 2-228-88108-2).
^ J. et Th. Tréfouël, F. Nitti et D. Bovet, « Activité du p.aminophénylsulfamide sur l’infection streptococcique expérimentale de la souris et du lapin », dans C. R. Soc. Biol., vol. 120, 23 novembre 1935, p. 756.
^ "history of medicine :: Medicine in the 20th century -- Encyclopedia Britannica". britannica.com. Retrieved 17 January 2014.
^ "BAD HEALTH – Elixir Sulfanilamide | The Blog of Bad". blogofbad.wordpress.com. Retrieved 17 January 2014.
^ "History of WWII Medicine". web.archive.org. Retrieved 2014-04-04.
^ "Trade of Sulfonamides". Massachusetts Institute of Technology. Retrieved 26 October 2013.
^ "Pediazole: Indications, Side Effects, Warnings - Drugs.com". drugs.com. Retrieved 17 January 2014.
^ Brayfield, A, ed. (2 February 2011). "Sulfonamides and diaminopyrimidines". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 28 March 2014.
^ Tilles SA (August 2001). "Practical issues in the management of hypersensitivity reactions: sulfonamides". Southern Medical Journal 94 (8): 817–24. doi:10.1097/00007611-200108000-00013. PMID 11549195.
^ Slatore CG, Tilles SA (2004). "Sulfonamide hypersensitivity". Immunology and Allergy Clinics of North America 24 (3): 477–490, vii. doi:10.1016/j.iac.2004.03.011. PMID 15242722.
^ Knowles S, Shapiro L, Shear NH (2001). "Should Celecoxib Be Contraindicated in Patients Who Are Allergic to Sulfonamides?". Drug Safety 24 (4): 239–247. doi:10.2165/00002018-200124040-00001. PMID 11330653.
^ Veroni M. "ALLERGIES TO SULFONAMIDE ANTIBIOTICS AND CROSS-REACTIVITIES" (PDF). Western Australian Therapeutic Advisory Group. Retrieved 2014-02-07.
^ Brackett CC, Singh H, Block JH; Singh, H; Block, JH (July 2004). "Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group". Pharmacotherapy 24 (7): 856–70. doi:10.1592/phco.24.9.856.36106. PMID 15303450.
^ Harrison's Principles of Internal Medicine, 13th Ed. McGraw-Hill Inc. 1994. p. 604.

External links

List of sulfonamides
Author of "The Demon under the Microscope," a history of the discovery of the sulfa drugs
A History of the Fight Against Tuberculosis in Canada (Chemotherapy)
Presentation speech, Nobel Prize in Physiology and Medicine, 1939
The History of WW II Medicine
"Five Medical Miracles of the Sulfa Drugs." Popular Science, June 1942, pp. 73–78.
http://www.life.umd.edu/classroom/bsci424/Chemotherapy/AntibioticsHistory.htm - A history of antibiotics

UpToDate Contents

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English Journal

Metal-based biologically active azoles and β-lactams derived from sulfa drugs.

Ebrahimi HP1, Hadi JS2, Almayah AA3, Bolandnazar Z4, Swadi AG5, Ebrahimi A6.
Bioorganic & medicinal chemistry.Bioorg Med Chem.2016 Mar 1;24(5):1121-31. doi: 10.1016/j.bmc.2016.01.041. Epub 2016 Jan 21.
Metal complexes of Schiff bases derived from sulfamethoxazole (SMZ) and sulfathiazole (STZ), converted to their β-lactam derivatives have been synthesized and experimentally characterized by elemental analysis, spectral (IR, (1)H NMR, (13)C NMR, and EI-mass), molar conductance measurements and ther
PMID 26833242

Synthesis of Some Novel 2-Amino-5-arylazothiazole Disperse Dyes for Dyeing Polyester Fabrics and Their Antimicrobial Activity.

Gaffer HE1, Fouda MM2,3, Khalifa ME4,5.
Molecules (Basel, Switzerland).Molecules.2016 Jan 21;21(1). pii: E122. doi: 10.3390/molecules21010122.
The present work describes the synthesis of a series of four novel biologically active 2-amino-5-arylazothiazole disperse dyes containing the sulfa drug nucleus. The structures of the synthesized thiazole derivatives are confirmed using UV-spectrophotometry, infrared and nuclear magnetic resonance t
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Time-dependent hormesis of chemical mixtures: A case study on sulfa antibiotics and a quorum-sensing inhibitor of Vibrio fischeri.

You R1, Sun H2, Yu Y3, Lin Z4, Qin M2, Liu Y5.
Environmental toxicology and pharmacology.Environ Toxicol Pharmacol.2016 Jan;41:45-53. doi: 10.1016/j.etap.2015.10.013. Epub 2015 Nov 10.
Sulfa antibiotics (SAs) and quorum-sensing inhibitor (QSI) may pose potential ecological risks because mixed using of them has been proposed to inhibit bacteria from generating antibiotic resistance. This study investigated the time-dependent hormesis of single and binary mixtures of QSI and SAs of
PMID 26645135