Sulphonamides are antibacterial agents that work by competitively inhibiting the enzyme dihydropteroate synthetase, blocking the bacterial synthesis of folic acid. They are structural analogues of para-aminobenzoic acid (PABA), which is involved in folic acid synthesis. The key features required for antibacterial activity include the sulphanilamide skeleton and amino and sulphonyl groups at the 1 and 4 positions on the benzene ring. While sulphonamides were historically important antibiotics, their use has decreased with the availability of other drugs such as penicillin that are often more effective.

1. By : Hafiz Muhammad Attaullah

2.  Introduction
 Mechanism of action
 Structure
 Structure activity relationship(SAR)
 Physico-chemical Properties of sulphonamides

3.  One of the oldest antibacterial agents used to combat infection
 Used for coccal infection in 1935
 They are bacteriostatic because it inhibits bacterial synthesis of folic
acid
 Clinical usefulness has decreased because of the effectiveness of
other antibiotics and penicillin

4.  The sulphonamides are bacteriostatic antibiotics with a wide
spectrum action against most gram-positive bacteria and many
gram-negative organisms.
 Actually it was found to be the metabolic product of Prontosil,
which is responsible for antibacterial activity, and this has given
the initiation to develop sulphonamides as antibacterial agents.

5.  Bacteria synthesize their own folic acid of which p-
aminobenzoic acid(PABA) is a constituent, and is taken up by
the medium.
 Sulphonamides are structural analogues of PABA, inhibit
bacterial folate synthase and formation of folate get inhibited.
 Sulphonamides competitivily inhibit the PABA with pteridine
residue to form dihydropteroic acid which conjugates with
glutamic acid to produce dihydrofolic acid.
 Sulphonamide altered folate which is metabolicaly injurious.

11.  The major features of SAR of sulphonamides include the following:
 Sulphanilamide skeleton is the minimum structural requirement for
antibacterial activity.
 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.

12.  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.

13.  With substituents imparting electron-rich characters to SO2 group,
bacteriostatic activity increases.
 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.

14.  The active form of sulphonamide is the ionized, maximum activity
that is observed between the pKa values 6.6–7.4.
 Substitutions in the benzene ring of sulphonamides produced inactive
compounds.
 Substitution of free sulphonic acid (–SO3H) group for sulphonamido
function destroys the activity, but replacement by a sulphinic acid
group (–SO2H) and acetylation of N-4 position retains back the
activity

15.  Absorbed rapidly from the GIT (except topically used ).
 Peak plasma levels are achieved in 2-6hrs.
 Widely distributed and pass through BBB as well as placental barrier.
 Metabolized as acetylated conjugates in liver.
 Excreted through the glomerular filtration in urine.

16. Individual sulfonamides:
1. Well absorbed orally, short-acting: Sulfadiazine, Sulfadimidine,
Sulfisoxazole, Sulfamethoxazole
2. Well absorbed orally, long-acting: Sulfamethopyrazine
3. Poorly absorbed in GIT: Sulfasalazine
4. Used topically: Silver sulfadiazine

17.  Urinary tract infections
 Upper respiratory tract infections
 Nocardiosis
 Sulfasalazine in IBD
 Sulfacetamide in bacterial conjunctivitis & trachoma
 Silver sulfadiazine for prevention of infection of burn wounds .

18.  Hypersensitivity reactions
 Crystalluria, Hematuria, Renal obstruction.
 Allergic nephritis
 Haemolytic anaemia, aplastic anaemia, Thrombocytopenia
 Kernicterus in new born

21.  Acute or Complicated or recurrent urinary tract infections
especially in females
 Upper respiratory tract infections
 Toxoplasmosis
 Shigellosis
 Nocardiosis

22. Physico-chemical properties of sulphonamides are as follows:
1. Ionization of sulphonamides
2. pKa of sulphonamides
3. Absorption
4. Protein binding and Distribution
5. Excretion

23.  The suphonamide group SO2NH2 tends to gain stability.
 It loses a proton because the resulting negative charged ion is
resonance stabilized.
 The proton-donating form of the functional group is not charged so
can be characterized as an HA acid with carboxyl acids, phenols and
thiols.
 Loss of a proton can be associated with a pKa in a series.
 For example, sulfoxazole with pKa 5.0 indicates that it is slightly
weaker acid than acetic acid with pKa 4.8

24.  Despite of highly effective antibacterial agents, the pKa value of
sulphonamide group is 10.4 so pH at which 50% drug is ionized is
10.4 which is higher than the pH of urine(6.0) that is decreased
during infections.
 So all the sulphonamides insoluble, non-ionized and the salt
solutions coming out in

25. Clinically active sulphonamide pKa value:-
 Sulphadiazine 6.5
 Sulphamerazine 7.1
 Sulphamethazine 7.4
 Sulphasoxazole 5.0
 Sulphamethoxazole 6.1

26.  Sulphonamide and trimethoprim tend to be absorbed quickly after
metabolism.
 As sulphonamide can be found in urine just after 30min of the oral
dose.
 Some are poorly absorbed used in ulcerative colitis and reduction of
bowel flora and topical burn preparations e.g mafenide

27.  The sulphonamides vary widely in plasma protein binding e.g
sulfasoxazole 76%, sulphamethoxazole 60%, sulfadiazine 38% etc..
 The fraction that is bind to protein is not active but binding is
reversible so drug can become free and active.
 The more of drug is lipid soluble at physiological pH, more it will be
protein bond.
 Sulphonamides with similar pKa values having largest effect on
protein binding.
 Currently the relationship between protein binding and biological half
life is unclear

28.  Sulphonamides are primarily excreted as mixtures of parent drug its
N1-acetates and glucuronides which are highly inactive.
 Eg:sulfisoxazole is excreted as 80% unchanged while
sulphamethoxazole is excreted as 20% unchanged.Sulphadimethoxine
is excreted 80% as glucuronide.
 In patients with renal impairment, concentration of
sulphamethoxazole is greatly increased in plasma so a fixed
combination of sulphamethoxazole and trimethoprim should not be
used in such patients. As it would results in highly blockade pathway

29.  Define Sulphonamides and draw its structure ?
 Describe mechanism of action of sulphonamides ?
 State Structural activity relationship of sulphonamides ?
 State therapeutic uses of sulhpnamides ?
 Describe ph and pka effect of sulphonamides ?