SULPHONAMIDES

are first effective chemotherapeutic agents used for bacterial infection

in humans.
INTRODUCTION TO SULPHONAMIDES
Sulfonamides are the synthetic derivatives of sulfanilamide .These agents were the
first drugs to prevent and cure human bacterial infection successfully. They are
well-absorbed from the gastrointestinal tract.
Sulfonamides were originally active against a wide range of Gram-positive and
Gram-negative bacteria; however, the increasing incidence of resistance in bacteria
formerly susceptible to sulfonamides has decreased the clinical usefulness of the
drug.
They were introduced into medical practice even before the discovery of penicillins.

The sulphonamide sensitive micro-organisms require p-Amino benzoic acid

(PABA) for the synthesis of folic acid which is essential for the synthesis of DNA

and RNA. Sulphonamides block the biosynthesis of this folate coenzyme resulting

into the arrest of bacterial growth and cell division.

CLASSIFICATION OF SULPHONAMIDES

On the basis of duration of action

Short Acting : Sulfonamides with a half life less than 10 hours.

e.g. sulfamethazole,sulfanilamide.
Intermediate Acting: Sulfonamides with a half life between 10 to 24 hours.
e.g.sulfamethoxazole and sulfadiazine.
Long Acting : Sulfonamides with a half life longer than 24 hours.
e.g.Sulfadimethoxine and Sulfadioxine

On the basis of Pharmacological activity

Antibacterial agents : Sulphadiazine

Drugs used in dermatitis : Dapsone

Continued.
 From a therapeutic point of view

compounds which are readily absorbed and readily excreted

eg : sulphadiazine, sulphacetamide

compounds which are readily absorbed but slowly excreted

eg: sulphaphenozole, sulphadimetoxine .

compounds which are poorly absorbed

eg: sulphaguanidine, succinylsulphathiozole .

compounds with special indicatin

eg: marfanil, sulphapyridine

absolute compounds
eg: sulphanilamide, sulphathiazole
On the basis of Chemical structure
N-4 substituted Sulphonamides (pro drugs):

eg. Prontosil, Sulphaguanidine.

N-1 substituted Sulphonamides:

eg. Sulphadiazine,Sulphacetamide,Sulphadimidine, Sulphanilamide.

Both N-1 and N-4 substituted Sulphonamides:

eg. Succinyl sulphathiazole, Phthalyl sulphathiazole.

Non-aniline Sulphonamides:

eg. Mefenide .
H2N
4
1 SO2NH2

Continued.
SULPHANILAMIDE
 INTRODUCTION TO SULPHANILAMIDE

The compound p-aminobenzenesulphonamide, now known as sulphanilamide,

was first synthesized by Gelmo in 1908 as an intermediate in the study of azo

dyes.

Because of its high toxicity it not in practice now. But still used in veterinary practice

as antibacterial agent.

H2N SO2NH2
 SYNTHESIS OF SULPHANILAMIDE FROM ACETANILIDE
O O O

HN CH3 HN CH3 HN CH3

C l.S O 3 H C o n c .N H 4 O H
4 0 - 5 8 oC
Acetanilide

SO2Cl SO2NH2
p-acetamidobenzene sulphonyl chloride p-acetamidobenzene sulphonamide

NH2
H y d ro ly s is

SO2NH2
Sulphanilamide
SYNTHESIS OF SULPHANILAMIDE FROM SULPHANILIC ACID
O O O

HN CH3 HN CH3 HN CH3

C l.S O 3 H N H 3

- H C l

SO3H SO2Cl SO2NH2

H y d ro ly s is
(C H 3C O )2O
NH2
NH2

SO2NH2
SO H
SULPHACETAMIDE
INTRODUCTION TO SULPHACETAMIDE (Albucid)

It is white crystalline powder,it is soluble in water and CH3

alcohol, it is very soluble in hot water. Its aqueous
O
solution is acidic in nature.
NH
O
It readily absorbed from gastrointestinal tract. S
O
Sodium salt of sulphacetamide is quiet important, it
is used in the treatment of local infections of the eyes.

Sodium sulphacetamide is prepared by dissolving H2N

sulphacetamide in calculated amount of sodium
hydroxide solution and then evaporating the solution
to dryness. N-Sulphanilyl acetamide
SYNTHESIS OF SULPHACETAMIDE

SO2NH2

(C H 3C O )2O
CH3COHN SO2NHCOCH3
- H 2O

NH2 P a r tia l h y d r o ly s is - C H 3C O O H

O
O CH3
H2N S NH

O
SULPHAGUANIDINE
 INTRODUCTION TO SULPHAGUANIDINE

Sulphaguanidine is a white, fine crystalline powder,

NH2
soluble in dilute mineral acids, very slightly soluble
in water and ethanol.
HN NH
Used in the treatment of local intestinal infections. S O
O

Since it is slightly absorbed in intestinal tract, can

therefore given in relatively large doses.

Hot alkaline solution decomposes it to sulphanilamide

with the evolution of ammonia. NH2
SYNTHESIS OF SULPHAGUANIDINE

NH

CH3COHN SO2Cl + H2N Guanidine

NH2
4-Acetamidobenzene-1-sulphonyl chloride - H C l
HN
O NH2
CH3COHN S NH

O
- C H 3C O O H H y d r o ly sis /N a O H
HN
O NH2
H2N S NH

O
 SAR STUDY OF
SULPHONAMIDES
Prontosil is the lead structure, several thousands of
analogues of this compounds were synthesized and
tested for activity.
 High bacteriostatic activity was found in the compounds with the following general
structure

R O

N S NH2
H O

COOH NH2
The main difference between PABA
(Carboxyl moiety )and sulphanilamide
(Sulphonamide moiety) is their functional
group.
SO2NH2 SO2NH2

Continued.
Sulphanilamide contain strong electron withdrawing feature by virtue of the aromatic
SO2 moiety that renders the N-atom to which it is directly linked partially elecropositive
in character.
This, in turn, eventually enhances the acidity of the two H-atoms linked to the N-atom
thereby making this functional moiety (sulphonamide moiety) slightly acidic in nature
(pKa 10.4). In contrast, the pKa value of the carboxyl moiety of PABA, stands at 6.5.

Based on this concept, replacement of one of the H-atoms attached to the

sulphonamido N-atoms by an electron-withdrawing heteroaromatic nucleus (ring)
remarkably gave rise to the following two advantageous and useful features, namely :

(a) consistently improved antimicrobial activity,

(b) appreciably acidified the remaining H-atom and substantially increased

potency.
Thank
you