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Sulfonamide is a
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...
(a part of a
molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and b ...
) that is the basis of several groups of drugs, which are called sulphonamides, sulfa drugs or sulpha drugs. The original antibacterial sulfonamides are synthetic (nonantibiotic) antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the
anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...
sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based upon the antibacterial sulfonamides. Allergies to sulfonamides are common. The overall incidence of adverse drug reactions to sulfa antibiotics is approximately 3%, close to
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
; hence medications containing sulfonamides are prescribed carefully. Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine.


Function

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthase (DHPS), an enzyme involved in
folate synthesis Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
. 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. Sulfonamides are used to treat allergies and coughs, as well as having antifungal and antimalarial functions. The moiety is also present in other medications that are not antimicrobials, including thiazide
diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...
s (including hydrochlorothiazide,
metolazone Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water rea ...
, and indapamide, among others), loop diuretics (including
furosemide Furosemide is a loop diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It can be taken by injection into a vein or by mo ...
, bumetanide, and torsemide), acetazolamide,
sulfonylureas Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta ...
(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 broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine. The first sulfonamide, trade-named Prontosil, was a
prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...
. Experiments with Prontosil began in 1932 in the laboratories of
Bayer Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutic ...
AG, at that time a component of the huge German chemical trust
IG Farben Interessengemeinschaft Farbenindustrie AG (), commonly known as IG Farben (German for 'IG Dyestuffs'), was a German chemical and pharmaceutical conglomerate. Formed in 1925 from a merger of six chemical companies— BASF, Bayer, Hoechst, Agf ...
. 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 (working under the general direction of IG 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. 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 ''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occu ...
, including blood infections, childbed fever, and
erysipelas Erysipelas () is a relatively common bacterial infection of the superficial layer of the skin ( upper dermis), extending to the superficial lymphatic vessels within the skin, characterized by a raised, well-defined, tender, bright red rash, ...
, 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 Daniel Bovet, Federico Nitti, and Jacques and Thérèse Tréfouël, a French research team led by Ernest Fourneau at the
Pasteur Institute The Pasteur Institute (french: Institut Pasteur) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vacc ...
, that the drug was metabolized into two parts inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide. 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. The result was a sulfa craze. For several years in the late 1930s, hundreds of manufacturers produced myriad forms of sulfa. This and the lack of 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 broad-spectrum antibiotic available in the years before
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
, heavy use of sulfa drugs continued into the early years of
World War II World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the World War II by country, vast majority of the world's countries—including all of the great power ...
. 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 Franklin Delano Roosevelt (; ; January 30, 1882April 12, 1945), often referred to by his initials FDR, was an American politician and attorney who served as the 32nd president of the United States from 1933 until his death in 1945. As the ...
) and
Winston Churchill Sir Winston Leonard Spencer Churchill (30 November 187424 January 1965) was a British statesman, soldier, and writer who served as Prime Minister of the United Kingdom twice, from 1940 to 1945 during the Second World War, and again from ...
. 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 pKa 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 pKa, around 5–6, 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 Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry ...
. As of 2013, the
Republic of Ireland Ireland ( ga, Éire ), also known as the Republic of Ireland (), is a country in north-western Europe consisting of 26 of the 32 counties of the island of Ireland. The capital and largest city is Dublin, on the eastern side of the island. ...
is the largest exporter worldwide of sulfonamides, accounting for approximately 32% of total exports.


Varieties


Side effects

Sulfonamides have the potential to cause a variety of
adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...
s, including urinary tract disorders, haemopoietic disorders, porphyria and hypersensitivity reactions. When used in large doses, they may cause a strong allergic reaction. The most serious of these are classified as
severe cutaneous adverse reactions Severity or Severely may refer to: * ''Severity'' (video game), a canceled video game * "Severely" (song), by South Korean band F.T. Island See also

* * {{disambig ...
(i.e. SCARs) and include the Stevens–Johnson syndrome, toxic epidermal necrolysis (also known as Lyell syndrome), the DRESS syndrome, and a not quite as serious SCARs reaction,
acute generalized exanthematous pustulosis Acute generalized exanthematous pustulosis (AGEP) (also known as pustular drug eruption and toxic pustuloderma) is a rare skin reaction that in 90% of cases is related to medication administration. AGEP is characterized by sudden skin eruptions th ...
. Any one of these SCARs may be triggered by certain sulfonamides. 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%. 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. 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. 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"). 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 Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...
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. The most common manifestations of a
hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...
reaction to sulfa drugs are
rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...
and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens–Johnson syndrome, toxic epidermal necrolysis,
agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...
, hemolytic anemia,
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
, fulminant hepatic necrosis, and acute pancreatitis, among others.


See also

* Dihydropteroate synthase * Elixir sulfanilamide *
Hellmuth Kleinsorge Hellmuth Kleinsorge (* 12 April 1920 in Beuel; † 7 July 2001) was a German medical doctor. Life Hellmuth Kleinsorge studied medicine in Jena. In 1953, after his dissertation and habilitation, he became director of the "Medizinische Poliklinik ...
(1920-2001) German medical doctor * PABA * Timeline of antibiotics


References


External links


List of sulfonamides

Author
of ''
The Demon Under the Microscope ''The Demon Under the Microscope: From Battlefield Hospitals to Nazi Labs, One Doctor's Heroic Search for the World's First Miracle Drug'' is a 2006 nonfiction book about the discovery of Prontosil, the first commercially available antibacterial a ...
'', a history of the discovery of the sulfa drugs
A History of the Fight Against Tuberculosis in Canada (Chemotherapy)


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.

{{Diuretics Disulfiram-like drugs Hepatotoxins *