Sulphonamides

The term sulphonamides are employed as a generic name for the derivatives of para-amino benzene
sulphonamides(sulphonamides). The sulphonamide drugs were the first effective
chemotherapeutic agents to be employed systemically for the prevention and treatment of bacterial
infections in humans.
Spectrum:
Gram-Positive Bacteria: Staphylococcus aureus (including some methicillin-resistant strains,
though resistance is common). Streptococcus pyogenes, Streptococcus pneumonia.
Gram-Negative Bacteria: Escherichia coli, Klebsiella species, Proteus species, Haemophilus
influenza, Neisseria meningitides, Neisseria gonorrhoeae (though resistance is now widespread),
Shigella species, Salmonella species
Protozoa: Plasmodium falciparum, Toxoplasma gondii (causative agent of toxoplasmosis.
Classification:
On the basis of the site of action
 Sulphonamides for general infection: Sulphanilamide, Sulphapyridine, Sulphadiazine,
Sulphamethoxacine, Sulphamethoxazole.
 Sulphonamides for urinary tract infections: Sulphaisoxazole, Sulphathiazole.
 Sulphonamides for intestinal infections: Phthalylsulphathiazole, Succinyl sulphathiazole,
Sulphasalazine.
 Sulphonamides for local infections: Sulpahacetamide, Mafenamide, Silver sulphadiazine.
Sulphonamides for dermatitis: Dapsone, Solapsone.
 Sulphonamides in combination: Trimethoprim with Sulphamethoxazole.
On the basis of the duration of action:
 Extra long-acting sulphonamides (half-life greater than 50 h): Sulphasalazine,
Sulphaclomide, Sulphalene.
 Long-acting sulphonamides (half-life greater than 24 h): Sulphadoxine,
Sulphadimethoxine, Sulphamethoxy pyridazine, Sulphamethoxydiazine,
Sulphaphenazole, Sulphamethoxine.
 Intermediate-acting sulphonamides (half-life between 10–24 h): Sulphasomizole,
Sulphamethoxazole.
 Short-acting sulphonamides (half-life less than 20 h): Sulphamethiazole,
sulphaisoxazole.
 Injectables (soluble sulpha drugs): Sulphafurazole, Sulphadiazine, Sulphamethoxine.
Based on the chemical structure.
 N-substituted sulphonamide: Sulphadiazine, Sulphacetamide, Sulphadimidine.
 N-4 substituted sulphonamides (prodrugs): Prontosil.
 Both N-1 and N-4 substituted sulphonamides: Succinyl sulphathiazole and
phthalylsulphathiazole. Miscellaneous: Mefenide sodium.
Mechanism of Action
Sulphonamides act as structural analogs of para-aminobenzoic acid(PABA), a substrate for the
enzyme dihydropteroate synthase. Normally, PABA combines with dihydropteridine diphosphate
toform dihydropteroic acid, a precursor to folic acid. Sulphonamides

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competitively inhibit dihydropteroate synthase by
mimicking PABA,thereby blocking the incorporation
of PABA into dihydropteroic acid.This inhibition
prevents the formation of dihydropteroic acid, leading
to a decrease in the production of folic acid. Without
folic acid, bacteria cannot synthesize thymidine, purines,
and subsequently DNA, leading to impaired cell division
and bacterial growth.

Therapeutic Applications:
Urinary Tract Infections (UTIs): Due to their efficacy against common urinary pathogens like
E. coli. Respiratory Tract Infections: Effective against certain strains of S. pneumoniae and H.
influenzae. Nocardiosis: Sulphonamides, particularly sulfamethoxazole, are effective against
Nocardia infections. Toxoplasmosis: Often used in combination with other drugs (e.g.,
pyrimethamine) to treat T. gondii infections. Malaria: Sulfadoxine, in combination with
pyrimethamine (Fansidar), is used for malaria prophylaxis and treatment. Burns and Wounds:
Sulfonamide derivatives like silver sulfadiazine are applied topically to prevent bacterial infections
in burns.
Synthesis:
Prontosil:

Sulphanilamide:
Benzene on nitration yields nitrobenzene which on reduction gives aniline. p-Amino benzene
sulphonic acid is obtained by treating aniline with hot concentrated sulphuric acid which on
chlorination with phosphorus pentachloride gives p-aminobenzene sulphonyl chloride; and this on
amination with concentrated ammonia solution yields sulfanilamide

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The free and active amino function in sulphanilic acid is first protected by acetylation and the
resulting p-acetamido-benzene sulphonic acid is chlorinated with chlorosulphonic acid to obtain
paraacetamido benzene sulphonyl chloride. This on amination with concentrated ammonia
solution changes into its corresponding sulphonamide analog, which on hydrolysis results in the
formation of sulfanilamide.
Dose: 0.5 to 3 g daily; USP dose range 0.5 to 6 g daily

Sulphapyridine:
It is mainly used in the treatment of dermatitis herpetiformis for such patients who do not give a
positive response to dapsone. It is effective in pneumonia. Though more potent than sulfanilamide,
it is more toxic and has been replaced by sulfadiazine.
p-Acetamidobenzene sulphonyl chloride (ASC) is condensed with 2-aminopyridine using pyridine
as a solvent, followed by alkaline hydrolysis of the resulting product to yield sulfapyridine.
Dose: 0.5 to 3 g daily; USP dose range 0.5 to 6 g daily.

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Sulphadimidine:

It may be prepared from condensation of ASC and 2-Amino-4, 6-dimethylpyrimidine and then
Hydrolysis in an alkaline medium. 2-amino-4, 6-dimethyl pyrimidine is prepared by reacting
together the Lactim-form of acetylacetone and guanidine.
Dose : 3 g initially; subsequent doses up to 6 g per day in divided doses
Sulphamethoxazole:
Sulphamethoxazole is an oral Sulphonamide antibiotic, used in combination with Trimethoprim
to treat a variety of infections of the urinary Tract, Respiratory system, and gastrointestinal Tract.
Synthesis:

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Dose: Orally 2 g followed by 1 g every 8 h

Sulphadiazine:

It is used in combination with pyrimethamine for prophylaxis of cerebral toxoplasmosis. It is also

used in otitis media, rheumatic fever, chlamydia, Haemophilus influenza, bacterial meningitis and
UTIs.
Dose: 3 g initially; USP dose ranges 2 to 8 g daily.

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Sulphafurazole:
Its characteristics and therapeutic utilities are almost similar to those of sulfadiazine. It finds favour
in the treatment of various urinary-tract infections. It may be used in the form of topical
preparations for the treatment of some infections, such as vaginitis caused by Hemophilus
vaginalis

It is prepared by condensing together p-acetamidobenzene sulphonyl chloride (ASC) with 5-

amino-3, 4-dimethyl isoxazole and hydrolysing the resulting product in an alkaline medium.
Dose: 2 to 4 g initially ; oral, followed by 4 to 8 g a day in 4 to 6 divided doses.
Structure-Activity Relationship of Sulphonamides:

1. Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity.

2. The amino- and sulphonyl-groups on the benzene ring are essential and should be in 1 and
4 position.
3. Sulphur atom should be directly linked to the benzene ring.
4. Replacement of benzene ring by other ring systems or the introduction of additional
substituents on it decreases or abolishes its activity.
5. Exchange of the –SO2 NH group by –CONH reduces the activity.

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 6. On N-1-substituted sulphonamides, activity varies with the nature of the substituent at the
amino group. With substituents imparting electron-rich characters to SO2 group,
bacteriostatic activity increases.
7. Heterocyclic substituents lead to highly potent derivatives, while sulphonamides, which
contain a single benzene ring at N-1 position, are considerably more toxic than heterocyclic
ring analogues.
8. The free aromatic amino groups should reside para to the sulphonamide group. Its
replacement at ortho or meta position results in compounds devoid of antibacterial activity.
9. Substitutions in the benzene ring of sulphonamides produced inactive compounds.
10. Substitution of free sulphonic acid (–SO3 H) group for sulphonamido function destroys the
activity, but replacement by a sulphinic acid group (–SO2 H) and acetylation of N-4
position retains back the activity.

References
 Lectures by Dr. Mohsin Abbas Khan
 Textbook of Medicinal Chemistry—V. Alagarsamy.
 Medicinal Chemistry— Ashutosh Kar.
 Medicinal Chemistry—D. Sri Ram

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