The term sulfonamides also known as (sulphonamides, sulfa drugs or sulpha drugs) are used for are a group of drugs ranging in clinical use from antibacterial to diuretic activity that share the sulfonamide functional group. Chemically, the sulfonamide functional group is -S (=O)2-NH2 , i.e. a sulfonyl group connected to an amine group. The original sulfonamides were synthetic antimicrobial agents but now newer groups have been developed from them . .The journey of these drugs is a remarkable one and their discovery represents one of the important breakthroughs of medicine of the 20th century

1. NIDA SEHAR
MS (PHARMACOLOGY) & MBA (Finance)
nidasehar19@yahoo.com

2.  The term sulfonamides also known as (sulphonamides, sulfa drugs or sulpha drugs) are used for are a group of
drugs ranging in clinical use from antibacterial to diuretic activity that share the sulfonamide functional group.
SULFONAMIDE FUNCTIONAL GROUP
 Chemically, the sulfonamide functional group is -S (=O)2-NH2 , i.e. a sulfonyl group connected to an amine
group.
 The original sulfonamides were synthetic antimicrobial agents but now newer groups have been developed from
them .
 .The journey of these drugs is a remarkable one and their discovery represents one of the important
breakthroughs of medicine of the 20th century

3. DYES
 Dyes are used for coloring various items such as our clothes, our furnishings, our accessories and hair.
 The different shades are attributed to the combination of a variety of chemicals natural or manmade molecules
 The discovery and exploitation of these very dyes is responsible for the creation and growth of the
biggest chemical industries of the world.
NATURAL DYES
 The earliest attempts of practice of chemistry that have been documented in 3000 BC are the extraction and
preparation of dyestuffs by the Chinese.
 Complicated extraction procedures were established to extract the dyes from plant material.
 The other problems were
 Pre treatment of fabric with mordants to make the colours hold.
 Limited range of colors
 Fast colors.

4.  In the late 1700’s synthetic dyes were created.
 The first among them was the triply nitrated picric acid which gave a strong yellow shade .
 It’s major drawback was that it was explosive in nature.
Picric acid
 In 1868 and 1880 synthetic alizarin (red dye) and synthetic indigo were discovered respectively
 In 1856 the first multistep synthesis of an organic compound took place when William Henry Perkins
accidentally discovered purple dye “muave “ from coal tar.
 By the end of 19th century around two thousand such dyes had been developed.
 These are collectively known as coal tar or aniline dyes.

5.  This dye manufacturing industry became the forerunner to an organic chemical
enterprise.
 The major contributor was Germany.
 The reason for Germany’s supremacy was collaboration between industries and
universities.
 Knowledge of the molecular structure of organic compounds and scientific
understanding of the chemical steps in the reactions of organic synthesis, paved the
way for scientists to develop the sophisticated technology required for modern day
pharmaceuticals.
 The three most important German companies were Badische, Anilin and Soda
Fabrik (BASF),Hoechst and Bayer.
 These three accounted for nearly half of the global market by 1881.

6.  In the earlier twentieth century the German and Swiss chemical industries
started to prosper from their investment in manufacturing of dyestuffs not
just financially but also in the form of a wealth of chemical knowledge, of
experience with large scale chemical reactions and of techniques for
separation and purification that were essential for expansion into new
chemical business of pharmaceuticals.
 When Perkins invented the dye muave in 1856 the average life
expectancy in Britain was forty five years which soared a century
later to seventy for males and seventy nine for females.
 The reason behind this was the development were molecules of medicinal
chemistry known as antibiotics and two German chemists and a pathologist.

7. 
 Medcinal herbs have been used for thousands of years to heal wounds, cure sickness and relieve pain. However
few effective remedies were known for treatment of bacterial infections. Even small cuts or wounds could turn life
threatening.
 The discovery of phenol by Joseph Lister shrinked the mortalty rate from infections.But it couldn’t stop
infection once it started.
 Influenza pandemic of 1918-1919 killed more than twenty million people worldwide. Cerebrospinal
meningitis had a mortality rate of about 50 % More than 2000 mothers died in childbirth annually from
Puerperal sepsis.
 This led to investigation of immunity providing methods in the form of vaccination.
 In the late nineteenth century renowned German medical researcher Paul Ehrlich was conducting
experiments on different coal tar dyes. He noted that these could stain some tissues and
microorganisms but not others. On the basis of this observation he proposed magic bullet approach.

8. 
 The first success was with a dye trypan red I which acted against trypanosomes (protozoic parasite) in laboratory
rats but it was not effective against the type responsible for causing human sleeping sickness. He continued
undeterred in his search for the magic bullet.
 In 1909, after several years of painstaking research beginning in 1903 on organoarsenic compounds,a
breakthrough occurred when he found that his compound 606, Arsphenamine (Salvarsan) , was
effective against the trypanosomes that cause syphilis.
 First marketed in 1910 by Hoechst Dyeworks Ehrlich’s “magic bullet” launched a medical practice that
Ehrlich called chemotherapy. Later, another chemical product, Atabrine, was found to be useful for
treating malaria.

9.  Gerhard Johannes Paul Domagk (1895-1964), was a German biochemist responsible
 for analyzing thousands of chemicals for their antibacterial properties.
 In 1927, the giant German chemical cartel I.G. Farben of whom Bayer was a part
decided to screen for medical activity the various dyestuffs that it was developing.
 In 1932 the Bayer team believed that coal-tar dyes which have ability to bind
preferentially to bacteria and parasites might be used to attack harmful organisms
in the body without causing damage to host healthy tissue.
 He focused on azo dyes, which have ability to attach strongly to protein in fibers or leather reasoning
that they could also attach themselves to the bacterial protein resulting in their inhibiting if not killing.
 They finally found an orange red dye sulfamidochrysoidine synthesized by two chemists working for
Farben, Fritz Mietzsch and Josef Klarer.
 On slight changing of chemical makeup the dye of active against streptococci in mice.
 It was named Streptozan but soon changed its name to Prontosil. The first sulfonamide approved for
systemic use.
 Its first human testing was according to one report by a Düsseldorf physician to a 10-month-old baby
boy dying of staphylococcal septicemia or according to other reports Domagk used Prontosil on his
own daughter, who was dying from a streptococcal infection following a pin prick. But wherever the
first use clinical trials with the drug were a resounding success.

10.  It was discovered again by Bovett Federico Nitti and J. and Th. Jacques Tréfouël.
 Later a French research team led by Ernest Fourneau at the Pasteur Institute, was struck by two unusual aspects
of Prontosil.
 It is active in vivo but not in vitro.
 Patients on whom drug is used do not excrete it but rather, they excrete a simpler molecule, sulfanilamide (p-
aminobenzenesulfonamide).
 They concluded that Prontosil is cleaved at its nitrogen–nitrogen double bond upon ingestion releasing from the
inactive dye portion sulfanilamide (p-aminobenzenesulfonamide). The discovery helped establish the the
concept of "bioactivation“
 This also destroyed Bayer’s dreams of enormous profit from Prontosil as the active molecule sulfanilamide (or
sulfa) had first been reported by the Austrian chemist Paul Gelmo, who had synthesized it in1908.
 It had since been used as a dye intermediate but its therapeutic properties had went unnoticed. Its patent had
since expired.

12.  The result of this discovery was a sulfa craze. In the late 1930s and early
1940’, hundreds of pharmaceutical firms throughout Europe and the United
States produced more than 5000 such compounds .
 Among them only a few proved to be useful. Notable among them are:
 Sulfapyridine :Used in pneumonia (it was used to treat Winston Churchill
when he came down with pneumonia during World War II)
 Sulfathiazole:Used in both pneumonia and staphylococcal infections
 Sulfadiazine: Used against pneumonococcal, streptococcal, and
staphylococcal bacteria
 Sulfaguanadine:Used against dysentery.
 In 1937—the first year of real commercial production output in USA totaled
about 350,000 pounds which had doubled by 1940.
 By 1942, it topped an estimated 10 million pounds.

13.  In 1936 English doctors had stunning results when they used prontosil to treat
childbed fever and meningitis.
 Dramatic proof of the effectiveness of this new agent was provided
during an outbreak of meningitis in the French Foreign Legion in
Nigeria.While sulfanilamide was available, there was an 11% mortality
rate. After the supply was exhausted, mortality climbed to 75%.:
 In 1936, tests in United States initially at Johns Hopkins Hospital in
Baltimore, MD, and Western Pennsylvania Hospital in Pittsburgh,
showed that it was effective in treating various streptococcic
infections and pneumonia.
 It further gained wide publicity in the United States in 1936 when it was
used to treat President Franklin Delano Roosevelt’s son Franklin, Jr., who
was severely ill from a streptococcic infection.
 During World War II, U.S. troops were issued a first-aid kit containing sulfa pills and powder. They
were told to sprinkle it on any open wound and to take pills if they were wounded.
 The use of the drugs to fight dysentery allowed U.S. forces to overcome a disease that at times severely
hampered the Japanese fighting in the South Pacific

14.  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.

15.  In June 1937, there was increased demand in the Southern USA for sulfanilamide in liquid formulation.
 Therefore S. E. Massengill Co., a small drug formulator in Bristol, TN, decided to prepare liquid form of
the drug rather than the usual pill or injection.
 The company's chief chemist and pharmacist, Harold Cole Watkins, experimented and decided that
diethylene glycol was best solvent for sulfanilamide.
 Testing was only done on the mixture for flavor, appearance, and fragrance but not for toxicity which
was in accordance with US Food and Drug Law (1906).
 One aspect that was ignored was that diethylene glycol an antifreeze is a deadly poison.
 633 shipments were sent all over the country.
 The American Medical Association (AMA) received reports from physicians all over the country in that
an unfamiliar sulfanilamide compound was responsible for a number of deaths.
 Massengill Co. was asked to submit the composition of the compound.
 Diethylene glycol was determined as the toxic ingredient .
 The victims of Elixir Sulfanilamide poisoning were ill for about 7 to 21 days. All of them exhibited
similar symptoms, characteristic of kidney failure: stoppage of urine, severe abdominal pain, nausea,
vomiting, stupor, and convulsions. They suffered intense and unrelenting pain.
 No antidote existed at that time.

16.  In 1937 the law did not prohibit the sale of dangerous, untested, or poisonous drugs.
 Dr. Samual Evans Massengill, the firm's owner, said: "My chemists and I deeply regret the fatal results,
but there was no error in the manufacture of the product. We have been supplying a legitimate
professional demand and not once could have foreseen the unlooked-for results. I do not feel that
there was any responsibility on our part.“
 He was only charged for misbranding. The term “elixir” implied that the solvent in the bottle was ethyl
alcohol. And at that time dug dispensers were liable by law to label their products accurately but
testing for safety was not required..
 The company was only fined $16,800 for false labeling .
 The firm's chemist apparently did not share this feeling; Harold Watkins committed suicide after
learning of the effects of his latest concoction.
 However this Elixir experience did hasten enactment of the 1938 Federal Food, Drug, and Cosmetic
Act.
 The New Drug section, added to prevent such tragedies, gave the United States a new system of drug
control which provided superior protection while stimulating medical research and progress.
 According to this law manufacturers were required to test any new drug for safety and report the
results to the U.S. Food and Drug Administration.

17.  During the decade or so after their introduction, however, they saved tens of thousands of lives. And
they ushered in the era of modern chemotherapy by spurring research on many other antimicrobial
drugs.
 By the end of the war, though, sulfa drugs were largely eclipsed by penicillin and, later, by other
antibiotics.
 Sulfonamides had serious drawbacks. Because of their typical low solubility, they could be deposited in
the kidney and cause damage to it. Also, bacteria tend to build up a resistance to them, making them
ineffective.
 Sulfa drugs still play a role in modern medicine, albeit relatively minor. They are prescribed, for
example, for treating urinary tract, vaginal, and eye infections, as well as for veterinary applications.
 Sulfonamides that are currently available include:
 Sulfisoxazole (Urinary tract infections)
 Sulfamethoxazole (Urinary tract infections)
 Sulfadoxine
 Sulfasalazine (Ulcerative colitis, enteritis, and other inflammatory bowel disease)
 Sodium sulfacetamide (Bacterial conjunctivitis and as adjunctive therapy for trachoma.)
 Mafenide acetate,
 Silver sulfadiazine (Prevention of infection of burn wounds.)

18.  Trimethoprim, is a trimethoxybenzyl pyrimidine, which selectively inhibits bacterial dihydrofolic
acid reductase, responsible for converting dihydrofolic acid to tetrahydrofolic acid, a step leading
to the synthesis of purines and ultimately to DNA .
 Pyrimethamine, is a benzyl pyrimidine,that selectively inhibits dihydrofolic acid reductase of
protozoa.
 Any of them in combination with a sulfonamide blocks sequential steps in folate synthesis,
resulting in marked improvement (synergism) of the activity of both drugs.
 The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide
alone.
 EXAMPLES:
 Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of
acute toxoplasmosis.
 Sulfadoxine long-acting sulfonamide currently available only as a combination
formulation with pyrimethamine (Fansidar), a second-line agent in the treatment of
malaria.
The combination of Sulfamethoxazole and trimethoprim (Co-trimoxazole) .It is effective in urinary
tract infections, acute exacerbations of chronic bronchitis, alternative of floroquinolone in
treatment of shigella, sensitive sttrains of salmonella typhi, , acute diarrhea due to E-coli etc.

19.  The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the
sulfonamide group. They have laid the foundation of newer drug groups based on the antibacterial
sulfonamides.
 Sulfonylureas (anti-diabetic agents)
 Diuretics
 Anticonvulsants
 Antiretrovirals
 Hepatitis C antivirals
 Miscellaneous

20.  Acetohexamide
 Carbutamide
 Chlorpropamide
 Glibenclamide (glyburide)
 Glibornuride
 Gliclazide
 Glyclopyramide
 Glimepiride
 Glipizide
 Gliquidone
 Glisoxepide
 Tolazamide
 Tolbutamide
https://www.researchgate.net/figure/260907570_fig1_Figure-1-Some-selective-sulfonylureas-for the
treatment-of-type-2-diabetes

21.  Acetazolamide
 Bumetanide
 Chlorthalidone
 Clopamide
 Furosemide
 Hydrochlorothiazide
 Indapamide
 Mefruside
 Metolazone
 Xipamide
 http://www.ebmconsult.com/articles/chlorthalidone-hydrochlorothiazide-
differences-mechanism-of-action

22. ANTI RETROVIRALS
 Amprenavir (HIV protease inhibitor)
 Darunavir (HIV protease inhibitor)
 Delavirdine (non-nucleoside reverse transcriptase inhibitor)
 Fosamprenavir (HIV protease inhibitor)
 Tipranavir (HIV protease inhibitor)
HEPATITIS C ANTIVIRALS
 Asunaprevir(NS3/4Aprotease inhibitor)
 Beclabuvir(NS5BRNA polymerase inhibitor)
 Dasabuvir(NS5B RNA polymerase inhibitor)
 Grazoprevir (NS3/4A protease inhibitor)
 Paritaprevir(NS3/4A protease inhibitor)

23.  Apricoxib (COX-2 inhibitor)
 Bosentan (endothelin receptor antagonist)
 Brinzolamide (carbonic anhydrase inhibitor for glaucoma)
 Celecoxib (COX-2 inhibitor)
 Dofetilide (class III antiarrhythmic)
 Dorzolamide (anti-glaucoma carbonic anhydrase inhibitor)
 Dronedarone (class III antiarrhythmic)
 Ibutilide (class III antiarrhythmic)
 Parecoxib (COX-2 inhibitor)
 Probenecid(uricosuric)
 Sotalol (β blocker)
 Sulfasalazine (anti-inflammatory agent)
 Sumatriptan (antimigraine triptan)
 Tamsulosin(α blocker)
Ethoxzolamide (anticonvulsant)
 Sultiame (anticonvulsant)
 Topiramate (a sulfamate, not a true sulfonamide) (anticonvulsant)
 Zonisamide (anticonvulsant)

24.  Le Couteur P. and Burreson J. Napoleon’s Buttons: How 17 molecules changed
history : Jeremy P. Tarcher / Penguin, 2004
 Katzung B.G., Masters S.B. and Trevor A. J. Basic and Clinical Pharmacology Mc.
Graw Hill, 2012
 Kiefer D. Miracle Medicines : The advent of the sulfa drugs in the mid-1930s gave physicians a
powerful weapon. Today's Chemist a work : American Chemical Society June 2001
 Wikipedia
 Ballentine C. Sulfanilamide Disaster : Taste of Raspberries, Taste of Death The 1937 Elixir
Sulfanilamide Incident : FDA Consumer Magazine June 1981

25. THANKS