Sulfonamides are antibacterial drugs that work by interfering with bacterial synthesis of folic acid. They are structural analogues of para-aminobenzoic acid (PABA) that bind to and inhibit the enzyme dihydropteroate synthase. This document discusses the mechanism of action, classification, structure-activity relationships, and properties of sulfonamides. It provides examples of commonly used sulfonamides and details their structures, mechanisms, and applications in treatment. The document also addresses issues like ionization, crystalluria, and dissociation constants that are important for understanding sulfonamide properties and use.

1. ANTIBACTERIAL
SULPHONAMIDES

2. TABLE OF CONTENTS
 INTRODUCTION
 MECHANISM OF ACTION
 CLASSIFICATION
 STRUCTURE ACTIVITY
RELATIONSHIP
 synthesis
 IONIZATION
 CRYSTALLURIAAND dissociation
constant
 Question bank
 End-up slide

3. INTRODUCTION
 Sulfonamides are generic name for the
derivatives of para amino benzene
sulfonamide.
 They are effective chemotherapeutic
agents used for the prevention and
treatment of bacterial infections in
human.
 Sulfonamides are bacteriostatic
antibiotics with a wide spectrum action.

4.  Sulfonamides are metabolic product of
prontosil (a dye) which is responsible for
antibacterial activity.

5. MECHANISM OF ACTION
 Many bacteria synthesize Folic acid in the
body.
 Of which PABA is a constituent.
 Sulfonamides are structural analogues of
PABA.
 Sulfonamides inhibits bacterial folate
synthase Folic acid not formed. Due to
this, number of metabolic reactions suffer.
 Sulfonamides inhibit PABA with pteridine
residue to form dihydropteroic acid.

6.  Dihydropteroic acid + Glumatic acid
 conjugation
 Dihydrofolic acid
 Sulfonamide act as altered PABA to form
tetrahydrofolic acid which is metabolically
injurious.
 Hence Trimethoprim is given with
sulfonamide which block this pathway
due to which tetrahydrofolate is not
formed.

7. Classification
 Orally absorbed drugs- sulfamethiazole ,
sulfisoxazole , sulfamethazine ,
sulfisoxazole acetyl , sulfapyridine.
 Topical – Mafenide acetate , silver
sulfadiazine.
 Orally non-absorbable drugs –
sulfadiazine , sulfadimidine.

8. 1. Orally absorbed drugs -
 Sulfamethiazole -
4-amino-N-(5-methyl-1,3,4-thiadiazol-
2-yl) benzene sulfonamide.

9.  Sulfisoxazole -
4-amino-N-(3,4-dimethyl-
5-isoxazole) benzene sulfonamide
Use – in treatment of UTI.

10.  Sulfisoxazole acetyl-
N-acetyl-N-(3,4-dimethyl-5-
isoxazolyl)sulfonamide

11.  Sulfamethazine

4-amino-N-(4,6-dimethyl pyrimidin-2-yl)
benzene sulfonamide.

12.  Sulfapyridine
4-amino-N-(2-pyridyl)benzene sulfonamide

13.  Sulfadiazine
4-amino-N-(2-pyrimidinyl)benzene
sulfonamide

14.  Sulfamerzine
4-amino-N-(4-methyl pyrimidin-2-yl) benzene
sulfonamide

15. 2. Topical drugs
 Mafenide

16.  Silver sulfadiazine

17.  Dapsone

18. 3. Orally non-absorbable drugs
 Sulfasalazine
4-[(3-carboxy-4-hydroxy phenyl)azo]-N-
pyridin-2-yl benzene.

19. sar of sulfonamides
 Major features are:-
 Sulfonamide skeleton is basic
requirement for activity.
 SO2 and NH2 group are essential at 1 and
4 position.

20.  Sulfur atom should be directly linked to the
benzene ring.
 Replacement of benzene ring by other ring
decreases the activity.
 Introduction of additional substituents
decreases or abolishes the activity.
 Exchange of SO2NH group by -CONH group
reduces the activity.
 Free aromatic group should reside on para
position, its replacement to ortho or meta
position devoids it from antibacterial
activity.

21.  Heterocyclic substituent lead to highly
potent derivatives, sulfonamides contin
single benzene ring at N-1 position, are
considerably more toxic than heterocyclic
analogues.
 Active form of sulfonamide are ionized,
hence maximum activity is observed at
Pka values 6.6-7.4

22. synthesis
 Sulfanilamide

24.  Sulfasalazine

25.  Trimethoprim

26. Ionization of sulfonamides
 The sulfonamide group, SO2NH2, tend to gain
stability if it loses a proton, because the
resulting negative charge is a resonance
stabilized.
 Since the proton donating form of a
functional group is not charged, we can
categorize it as an HA acid, along with
carboxyl groups, phenols and thiols.
 The loss of a proton can be associated with a
pka for all of the compounds in a series.

27.  Example – pka of sulfisoxazole (pka 5.0)
indicates that the sulfonamides is a
slightly weaker acid than acetic acid (pka
4.8).

28. Crystalluria and
 Sulfanilamides and their metaboites are
excreted almost entirely in kidney.
 pka of sulfonamido group of sulfonamide
is 10.4, so 50% drug is ionised at pH 10.4
 Unless the pH is above pka, the water
soluble salt is present.
 Urine has pH 6, essentially all of the
sulfanilamide is in relatively insoluble,
non-ionised form in kidneys.

29.  The sulfanilamide coming out of solution in
the urine and kidneys causes crystalluria.
 Early approaches to adjust the solubility of
sulfonamides were :-
1. Greatly increasing the urine flow.
2. Increasing the pH of urine.
3. Preparing derivatives of sulfanilamide
that have lower pka values, closer to the pH
of urine.
4. Mixing different sulfonamides to achieve
an appropriate total dose.

30. pka value of some ionisable
sulfonamides are:-
SULFONAMIDE pka
1. Sulfadiazine 6.5
2. Sulfamerazine 7.1
3. Sulfamethazine 7.4
4. Sulfisoxazole 5.0
5.
Sulfamethoxazole
6.1

31. question bank
 Give SAR of sulphonamides.
 Discuss the MOA of sulphonamides.
 Give SAR & MOA of sulphonamides
 Give the classification of sulphonamides with structure
& examples.
 Explain the rationale of co-trimaxazole combination &
outline the synthesis of isoniazid & ethambutol.
 Write structure, chemical name & SAR of Trimethoprim.
 Name any two sulphonamides which are used in
chemotherapy & burn therapy along with the structure &
chemical name.
 Classify sulphonamides on the basis of their site of
action. Give chemical name, structure, MOA &
application of sulfisoxazole

32.  Write structure, IUPAC name, synthesis & specific uses
of the following:-
◦ Sulphamethoxazole
◦ Sulphadiazine
◦ Trimethoprim
◦ Sulphacetamide
◦ Sulfathiazole
 Classify sulphonamides on the basis of duration of
action. Write their structures, IUPAC names & specific
uses. Discuss SAR of sulphonamides to reduce
“crystallurea”. Give synthesis of sulphanilamide.
 Give in general mode of action of sulphonamides.

33.  Give mechanism of action of sulphonamides.
Write structural modifications that can be used
to prevent crystalluria associated with
sulphonamide therapy.
 Write structure, IUPAC name, mode of action,
synthesis & uses of following:-
◦ Sulphanilamide
 Write mechanism of action of sulphonamides.
What is the relationship between structure &
activity of different sulphonamides.
 Write synthesis of trimethoprim or
sulphacetamide.
 Draw the structure & write chemical names of
sulfamethoxazole & sulphasalazine.

34. THANK YOU
PREPARED BY – MANJEET SINGH
RAMGADIYA
TOPIC – ANTIBACTERIAL SULFONAMIDES
SUBJECT – PHARMACEUTICAL
MEDICINAL CHEMISTRY II
DATE OF DELIVERY – 04/02/2016 &
05/02/2016
DELIVERED BY – MANJEET SINGH
RAMGADIYA