The document provides an overview of sulphonamides, the first effective chemotherapeutic agents for bacterial infections, detailing their mode of action, structure-activity relationships, classifications, and specific drugs such as sulfamethoxazole and trimethoprim. It explains how sulphonamides inhibit bacterial folic acid synthesis and categorizes them based on various criteria including site of action, pharmacokinetic properties, and chemical structure. Additionally, it highlights the therapeutic uses and properties of specific sulphonamides like sulfacetamide and dapsone.

1. SULPHONAMIDES
Presented by
ANJANA PAUDEL
Department of
B.pharmacy

2. INTRODUCTION
The sulphonamides were the first effective
chemotherapeutic agents to be employed systematically
for the treatment and prevention of bacterial infections in
humans.
It is found to be metabolic product of protonsil which is
rensponsible for antibacterial activity.
This has given initiation to develop sulphonamides as a
antibacterial agents.
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4. MODE OF ACTION
Folinic acid (N5 -formyl tetrahydrofolic acid, N5 , N10 -
methylene-tetrahydrofolic acid and N10 -
formyltetrahydrofolic acid) are the important co-enzyme
required for several biosynthetic pathways in human,
bacteria, animals and plants.
In absence of these folate coenzymes, for e.g thymidine
monophosphate (TMP) will not be available to form
nucleic acid hence result in stoppage of cell division.
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Sulfonamide and Trimethoprim acts as inhibitor of folinic acid
pathway and acts as bacteriostatic. They inhibit tetrahydrofolate
synthesis by inhibiting dihydro-pteroate synthase and folate
reductase respectively.

6. SAR OF
SULPHONAMIDES
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The major features of SAR of sulphonamides include the
following:
Sulphanilamide skeleton is the
minimum structural requirement for
antibacterial activity.

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The amino- and sulphonyl-groups on the benzene ring
are essential and should be in 1 and 4 position.
The N-4 amino group could be modified to be prodrugs,
which are converted to free amino function in vivo.

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 Sulphur atom should be directly linked to the 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 –SO2NH group by –CONH reduces the activity.
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.

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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.
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.
The active form of sulphonamide is the ionized, maximum activity that
is observed between the pKa values 6.6–7.4.

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Substitutions in the benzene ring of sulphonamides produced
inactive compounds.
 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.
The lipid solubility influences the pharmacokinetic and antibacterial
activity, and so increases the half-life and antibacterial activity in
vitro

11. CLASSIFICATION
Sulphonamides can be classified in various ways:
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.
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 Sulphonamides for local infections: Sulpahacetamide,
Mafenamide, Silver sulphadiazine.
 Sulphonamides for dermatitis: Dapsone, Solapsone.
 Sulphonamides in combination: Trimethoprim with
Sulphamethoxazole

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On the basis of the pharmacokinetic properties
 Poorly absorbed sulphonamides (locally acting
sulphonamides)—Sulphasalazine, Phthalylsulphathiazole,
Sulphaguanidine, Salicylazo sulphapyridine, Succinyl sulpha
thiazole.
Rapidly absorbed and rapidly excreted (systemic sulphanamides):
Sulphamethoxazole, Sulphaisoxazole, Sulphadiazine,
Sulphadimidine, Sulphafurazole, Sulphasomidine,
Sulphamethiazole, Sulphacetamide Sulphachlorpyridazine.

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Topically used sulphonamides: Sulphacetamide,
Mafenide, Sulphathiazole, Silver sulphadiazine.
On the basis of the pharamacological activity
 Antibacterial agents: Sulphadiazine, Sulfi soxazole.
Drugs used in dermatitis: Dapsone.

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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.

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Short-acting sulphonamides (half-life less than 20 h):
Sulphamethiazole, sulphaisoxazole.
Injectables (soluble sulpha drugs): Sulphafurazole,
Sulphadiazine, Sulphamethoxine.

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On the basis of 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, Phthalylsulphathiazole.
 Miscellaneous: Mefenide sodium.

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24. SULPHONAMIDE FOR TOPICAL
APPLICATION
Sulphacetamide
It is White in color.
 Highly soluble in water.
Highly soluble at biological pH 7.4
Used in the treatment of bacterial infections of urinary
tract.
DOSE :Dose for eyes, as drops 10%, 15%, 20%, and 30%;
in ointments 2.5% and 6% of Sulphacetamide
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SYNTHESIS
When sulphanilamide is treated with acetic anhydride
and subsequent selective,reductive deacylation of the
resulting acetamide gives sulphacetamide.

26. MODE OF ACTION
Sulfacetamide is a synthetic sulfanylacetamide derivative
with bacteriostatic activity.
Sulfacetamide inhibits bacterial folic acid synthesis by
competing with para amino benzoic acid with a broad
spectrum of action.
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27. SULPHONAMIDE FOR BURN
THERAPY
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 Silver sulfadiazine
The silver salt of sulfadiazine applied in a
water miscible cream base has proven to
be an
effective topical antimicrobial agent,
especially against Pseudomonas species.
Salt form is slightly soluble and does not
penetrate the cell wall but acts on the
external cell
surface.
 Effective than Silver nitrate and mefenide.

28. MODE OF ACTION
Silver sulfadiazine may act through a combination of the
activity of silver and sulfadiazine.
When this agent interacts with sodium chloride-containing
body fluids, silver ions are released slowly and sustainably
into wounded areas.
Ionized silver atoms catalyze the formation of disulfide bonds
leading to protein structural changes and inactivating thiol-
containing enzymes; silver ions may also intercalate DNA
thereby interfering with replication and transcription of
bacteria.
As a competitive inhibitor of para- aminobenzoic acid (PABA),
sulfadiazine inhibits bacterial dihydropteroate synthase,
thereby resulting in disruption of folic acid metabolism and
ultimately DNA synthesis
USES ; Indicated for the prevention and treatment of wound
sepsis in patients with second and third degree burns.December 7, 2020 28

29. SULFASALAZINE
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Sulphasalazine is a bright
yellow or brownish-yellow fine
powder.
 It is very slightly soluble in
alcohol, practically insoluble in
methylene chloride.
It dissolves in dilute solutions
of alkali hydroxides.
 It is used in the treatment of
ulcerative colitis.

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31. SULFADOXINE
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 Sulfadoxine is a sulfonamide
consisting of pyrimidine
having methoxy substituents
at the 5- and 6-positions and
a aminobenzenesulfonamido
group at the 4-position.
 In combination with the
antiprotozoal pyrimethamine.
 It is used as an antimalaria

32. FOLATE REDUCTASE
INHIBITORS
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 Trimethoprim
 Trimethoprim is a white or yellowish-
white powder.
 It very slightly soluble in water and
slightly soluble in ethanol.
 It is used as dihydrofolate reductase
inhibitor, effective against chloroquine
and pyrimethamine resistant strains of
Plasmodium falsiparum.

33. MODE OF ACTION
It works by blocking folate metabolism in some bacteria
which results in their death.
Trimethoprim binds to dihydrofolate reductase and
inhibits the reduction of dihydrofolic acid (DHF) to
tetrahydrofolic acid (THF).
Uses; is used in the treatment of bladder infections,
middle ear infections and travelers' diarrhea.
Originally introduced in combination with
sulfamethoxazole, it is now available as single agents.
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34. SULFAMETHOXAZOLE
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Properties
 It is crystal white or off-white powder.
It is practically odourless.
 It has half life 10hrs and may increased
in patient with renal failure.
 It is practically insoluble in water, ether
and chloroform.
 It is sparingly soluble in
ethanol,dissolves in dilute solution of
NaoH and in dilute acids.
 It is bacteriostatic sulfonamide
antibiotic that interferes with folic acid
synthesis in susceptible bacteria.
 It is generally given in combination
with trimethoprim that inhibits the
sequential step in bacterial folic acid
synthesis.
 It is used for urinary tract’s

35. MODE OF ACTION
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 Sulfamethoxazole is a structural analog of para-aminobenzoic acid (PABA).
 They inhibit the conversion of PABA to folic acid which interferes with normal
bacterial synthesis of folic acid.
 Hence, blockage of folate production inhibits the folate-dependent metabolic
processes for bacterial growth.

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 The carbamic acid , when lose the carbondioxide gives
5-methylisoxazol-3-amine.
 When 5-methylisoxazol3-amine is reacted with p-
acetamido benzene sulphonyl chloride (PABS) gives
sulphamethoxazole.

37. SYNERGISM OF
SULFONAMIDES AND FOLATE
REDUCTASE INHIBITORS
Blocking the biosynthesis of folate co-enzymes at
more than one point in the biosynthetic pathway of
bacteria will results in a synergistic antimicrobial
effect. It shows less chances of drug resistance.
Sulphonamides show synergistic action with
diaminopyrimidines such as trimethoprim.
 Trimethoprim is a potent and selective competitive
inhibitor of dihydrofolate reductase enzyme in
susceptible microorganisms, the enzyme required to
reduce dihydrofolate to tetrahydrofolate.
 Combination of sulphonamide and trimethoprim
produces sequential blocks in the synthesis of
tetrahydrofolate, the reduced form of folic acid that is
required for one carbon transfer reactions.December 7, 2020 37

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39. SULFAMETHOXAZOLE AND
TRIMETHOPRIM COMBINATION
The fixed dose combination of sulfamethoxazole and
trimethoprim in the dose ratio of 5:1 is called as
cotrimoxazole.
Sulfamethoxazole was selected for combining with
trimethoprim because both have nearly half life (~10hrs).
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Both trimethoprim and sulfamethoxazole works
sequentially in inhibition of enzyme systems in bacterial
synthesis of tetrahydrofolic acid.
Trimethoprim binds to bacterial dihydrofolate reductase
(in preference to human dihydrofolate reductase), also
preventing the formation of THF.

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Uses;
 It is used for urinary tract infections, MRSA skin infections, travelers'
diarrhea, respiratory tract infections, and cholera, among others.
 It may be used both to treat and prevent pneumocystis pneumonia in
people with HIV/AIDS. It can be given by mouth or intravenously. It is used
to prevent or treat Pneumocystis jiroveci pneumonia or Pneumocystis
carinii pneumonia (PCP), a very serious kind of pneumonia

42. DAPSONE
Properties
1. It is white or slightly yellow white-crystalline powder.
1. It is very slightly soluble in water.
2. It is soluble in acetone and dilute mineral
acids,sparingly soluble in alcohol.
3. It is used as folic acid synthesis inhibitor in the
treatment of leprosy and nocardiosis.
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43. SYNTHESIS OF DAPSONE
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44. REFERENCES
V.Alagarsamy- Textbook of Medicinal Chemistry
Textbook of medicinal chemistry-Ashutosh Kar
Slideshare.net
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