SULPHONAMIDES 1 Sulfonamide Antibacterials

SULPHONAMIDES
(Sulfonamides)
Introduction:
Sulphonamides, sulpha drugs, sulfonamides or sulfa drugs are the synthetic drugs which have
antibacterial properties and consist of sulfonamide functional group as part of their chemical
structure. They are the derivatives of para-aminobenzene sulphonamide (sulphanilamide).

Sulfonamide Functional Group Sulphanilamide

The sulphonamide drugs were one of the first effective chemotherapeutic agents to be employed
systemically for the prevention and treatment of bacterial infections in humans. The
sulphonamides are bacteriostatic antibiotics with a wide-spectrum action against most Gram-
positive bacteria and many Gram-negative organisms.
The advent of penicillins and, subsequently of other antibiotics has diminished the usefulness of
sulphonamides.
Examples of sulphonamide antibacterials include; Sulfamethoxazole, Sulfadiazine, Sulfasalazine,
Sulfacetamide, Sulfanilamide, Sulfapyridine, Sulfafurazole (Sulfisoxazole), etc.
Some sulfonamides are devoid of antibacterial activity. The anti-hyperglycemic sulfonylureas
(Glibenclamide, Glimepiride etc.) and thiazide diuretics (Chlorothiazide, Hydrochlorothiazide
etc.) are the drug groups based upon the antibacterial sulfonamides.
History:
The compound p-aminobenzenesulphonamide, now known as sulphanilamide, was first
synthesized by Gelmo in 1908 as an intermediate in the study of azo dyes. However, its therapeutic
value was actually ascertained many years before. Gerhard Domagk in 1935 screened a number of
azo-dyes for their antibacterial effects and observed that they were active against streptococci.
In 1935, a German firm prepared a red dye 4-sulphonamide-2′,4′-diamino-benzene or p′-sulphonyl
chrysoidine, and in 1938, Domagk suggested significant curative properties of this compound and
named it Prontosil.
Trefouel et al. (1935) at Pasteur Institute discovered that Prontosil breaks down in the tissues to p-
aminobenzenesulphonamide, now known as sulphanilamide, and suggested that the antibacterial
characteristics of the drug resided in this part of the molecule.
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It was observed that Prontosil is absolutely inactive in-vitro but possesses superb and excellent
antimicrobial activity in-vivo. This specific characteristic property of the drug eventually gained
overwhelming recognition and stimulated an extensive and intensive research activity focused onto
the sulphonamides. Later, Fuller (1937) further substantiated and confirmed this by isolating ‘free
sulphonamide’ from the blood and urine of subjects being treated with Prontosil.
In 1937, two British researchers prepared ‘sulphapyridine’ that was the first structural analogue of
‘sulphanilamide’. This particular compound proved to be a grand and tremendous success in curing
pneumonia. This discovery further paved the way for the synthesis and screening of hundreds of
derivatives of sulphanilamide, but only a few have proved to be potent medicinal compounds.
Nowadays, there exist a few typical sulphonamides and particularly the combinations (such as with
Trimethoprim or Pyrimethamine) are used for the management and treatment of bacterial
infections particularly the opportunistic infections.
Chemistry/Structure/Chemical Classification:
The term sulphonamides is employed as a generic name for the derivatives of para-aminobenzene
sulphonamide (sulphanilamide). They have sulfonamide functional group as part of their chemical
structure.

Sulfonamide Functional Group Sulphanilamide

Sulphonamide General Structure

Many structural modifications of sulphanilamide were made by the substitution of heterocyclic

aromatic nuclei at N-1 which yielded highly potent compounds. The substitution at N-4 is
comparatively rare and results in prodrugs.
The sulphonamides exists as white powder, mildly acidic in character, and they form water-soluble
salts with bases. The pH of sodium salts is usually very high. When given intramuscularly (IM),
the marked alkalinity causes damage to the tissues.
Sulphonamides can be classified in various ways such as; therapeutically, pharmacologically,
pharmacokinetically, chemically or on the basis duration of action. Chemically, Sulphonamides
can be classified as follows:
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1. N-1 Substituted Sulphonamides:

They are administered intravenously, intramuscularly or orally.

Generic name R R1

Sulphanilamide

Sulphapyridine

Sulphathiazole

Sulphacetamide

Sulphadiazine

Sulphadimidine
(Sulfamethazine)

Sulfafurazole
(Sulfisoxazole)

Sulphamethoxazole

Sulphadimethoxine

Sulphadoxine

They are further grouped as;

a. Short-Acting Sulphonamides: Sulphacetamide, Sulphadiazine, Sulphadimidine,
Sulfafurazole.
b. Intermediate-Acting Sulphonamides: Sulphamethoxazole.
c. Long-Acting Sulphonamides: Sulphadimethoxine.
d. Ultra Long-Acting Sulphonamides: Sulphadoxine.
SULPHONAMIDES 4 Sulfonamide Antibacterials

2. N-4 substituted Sulphonamides:

They are the prodrugs which are converted in-vivo to the active form. For example; Prontosil.

3. N-1 and N-4 Disubstituted Sulphonamides:

They are the prodrugs, which require in-vivo change to an N-4 unsubstituted form to show activity.

Generic name R R1

Succinyl sulphathiazole

Phthalyl sulphathiazole

4. Miscellaneous Sulphonamides:
Mostly they are topical sulphonamides. For example; Mafenide, Silver sulphadiazine, Dapsone.

Mode/Mechanism of Action of Sulphonamides:

Sulphonamides are bacteriostatic drugs and act by following mechanism.
 Sulphonamides are structural analogs and competitive antagonists of para-amino benzoic
acid (PABA).
 They compete with PABA for the enzyme dihydropteroate synthase, the bacterial
enzyme responsible for the incorporation of PABA into pteridine to form dihydropteric
acid intermediate which then converts to dihydrofolic acid (DHFA) by dihydrofolate synthase.
 Thus they block the synthesis of dihydrofolic acid (DHFA), and in turn tetrahydrofolic acid
(THFA) and folate cofactor.
 Folate cofactor acts as 1-carbon donor for the synthesis of nucleic acids (DNA, RNA).
 The result of blocking the biosynthesis of folate coenzymes in bacteria is that growth and
cell division are stopped (bacteriostatic action).
 Since mammalian cells use preformed folates from the diet, and since most bacteria cannot
use preformed folates and must synthesize their own folic acid, the sulphonamides,
therefore, demonstrate a selective toxicity to bacteria.
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Spectrum of Antibacterial Activity of Sulphonamides:

The sulphonamides are bacteriostatic antibiotics with a wide spectrum action against most Gram-
positive bacteria, many Gram-negative bacteria, Actinomycetes, Chlamydiae, and some protozoa,
such as Toxoplasma and Plasmodia.
Resistance to sulfonamides has increased among many of these organisms. While most Gram-
positive cocci and bacilli are still sensitive to sulfonamides, enterococci are resistant. Gram-
negative bacteria such as Escherichia coli, Enterobacter, Klebsiella, Proteus, Salmonella and
Shigella are sulfonamide sensitive, as are Neisseria and Haemophilus influenza. Mycobacterium,
Mycoplasma, Rickettsia and spirochetes are resistant.
Today sulfonamides are commonly used in combination with other antimicrobial agents such as
Trimethoprim and Pyrimethamine for the management and treatment of bacterial infections
particularly the opportunistic infections.
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SAR of Sulphonamides:

The major features of SAR of sulphonamides include the following:

Sulphanilamide Skeleton:
 Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity.
 The nitrogen of sulfonamide group (–SO2NH–) is designated as N-1 and that of aniline
amino group (–NH–) as N-4.
 The amino and sulphonyl groups on the benzene ring are essential and should be in 1 and
4 position.
 Sulphur atom should be directly linked to the benzene ring.
Isomeric Forms:
 The free aromatic amino groups should reside para to the sulphonamide group.
 The ortho- and meta-isomers are valueless therapeutically.
 Any other substitution on the aromatic ring either destroys or reduces the activity of the
drug.
Substitutions on Benzene Ring:
 Replacement of benzene ring by other ring systems or the introduction of additional
substituents on it decreases or abolishes its activity.
 Exchange of the sulfonamide group (–SO2NH–) by amide group (–CONH–) reduces the
activity.
 Additional substitutions in the benzene ring of sulphonamides produced inactive
compounds.
N-1 Substitutions:
 In 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.
 Heterocyclic substituents lead to highly potent derivatives. Sulphonamides which contain
a single benzene ring at N-1 position, are considerably more toxic than heterocyclic ring
analogs.
 Sulphonamides which have a non-substituted or mono-substituted N-1 nitrogen are acidic
and will readily form salts.
 The active form of sulphonamide is the ionized and the maximum activity is observed
between the pKa values 6.6–7.4.
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Replacement of Sulfonyl (–SO2–) Group:

 The antibacterial activity lies in the Sulfonyl (–SO2–) group.
 Removal of –SO2– group or replacement of –SO2– group with –SO3– group results in total
loss of antibacterial activity.
 Substitution of free sulphonic acid (–SO3H) group for sulfonamide function destroys the
activity, but replacement by a sulphinic acid group (–SO2H) retains the activity.
N-4 Substitutions:
 Free amino group at N-4 position is essential for activity.
 If an alkyl, alkoxy or other functional group is placed at N-4, no activity is observed. So,
any permanent substitution at N-4 results in loss of antibacterial activity.
 However, the N-4 amino group could be modified to produce prodrugs, which are
converted to free amino function in-vivo.
 So, acylation of N-4 position with dicarboxylic acids such as succinic acid or phthalic acid
retains the activity in the form of prodrugs.
 Sulphonamides bind to the basic centers of arginine, histidine, and lysine sites of proteins.
The binding groups are alkyl, alkoxy, and halides. The binding affects the activity of
sulphonamides; protein binding appears to modulate the availability of the drug and its
half-life.
 The lipid solubility influences the pharmacokinetic and antibacterial activity, and so
increases the half-life and antibacterial activity in-vitro.
Clinical Uses of Sulphonamides:
Oral Uses: Acute complicated urinary tract infections (UTIs), respiratory tract infections (RTIs),
malaria.
External Uses: Burns, sepsis, wounds, conjunctivitis, colitis, enteritis etc. Also used in vaginal,
eye, ear, intestinal and skin infections.
IV & IM Uses: In cases where oral administration is not feasible or possible such as Meningitis,
pneumonia etc.
Side Effects/ADRs/Contraindications of Sulphonamides:
 Headache, nausea, vomiting and epigastric pain.
 Allergic/hypersensitivity Reactions (2-5 %): Rashes, fever, urticaria, dermatitis, serum
sickness, agranulocytosis, hemolytic anemia, acute panreatitis. Steven-Johnson Syndrome
on prolonged use or heavy doses.
 Crystallurea: Sulphonamides cause severe kidney damage from crystals of sulphanilamide
forming in the kidney. Sulphanilamide is not very water-soluble and this leads to crystalluria.
 Hematotoxicity in G6PD (Glucose-6-phosphate dehydrogenase) Deficiency.
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SULFANILAMIDE

Synthesis of Sulfanilamide:

Uses of Sulfanilamide:
 It is used in skin infections.
 It is used in veterinary medicine as an antibacterial agent.
SULFACETAMIDE

Synthesis of Sulfacetamide:

Uses of Sulfacetamide:
 Used in the treatment of bacterial infections of urinary tract.
 Used in ophthalmic infections in the form of drops and ointments.
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SULFADIMIDINE (sulfamethazine)

Synthesis of Sulfadimidine:

Uses of Sulfadimidine:
 It is used for oral treatment of gastrointestinal infections, respiratory infections.
 It is used in veterinary medicine as an antibacterial agent.
SULFADIAZINE

Synthesis of Sulfadiazine:

Uses of Sulfadiazine:
 It is used in the treatment of urinary tract infections, otitis media and rheumatic fever.
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SULFAMETHOXAZOLE

Synthesis of Sulfamethoxazole:

Uses of Sulfamethoxazole:
 Used in combination with trimethoprim (co-trimoxazole) in various bacterial infections.
SULFAFURAZOLE (Sulfisoxazole)

Synthesis of Sulfafurazole:

Uses of Sulfafurazole:
 Used in the treatment of urinary tract infections.