Sulphonamides

Introduction

• Sulfonamides are synthetic chemotherapeutic agents.

• One of the oldest and widely used antimicrobial drugs prior
to the advent of antibiotics.
• They are bacteriostatic because it inhibits bacterial
synthesis of folic acid .
• Clinical usefulness has decreased because of the
effectiveness of other antibiotics like penicillin .
 Brief History
• 1854-1915 – Paul Ehrlich highlighted the relationship between selective
staining by dyes and antiprotozoal activity.
• 1932-I.G. Farben (dye company in Germany): Synthesis of azo dyes as
potential antimicrobials.

(Prontosil)
 1933-Gerhard Domagk
 Prontosil cured streptococcal infections in mice and rabbits
 Later shown to have an even broader application

 1935-Prontosil used against staphylococcal septicemia clinically.

(blood infection)
 Work on prontosil got published in 1935.
 1939-Domagk earned Nobel Prize in medicine
 Hitler did not allow him to accept
 Was later awarded the prize in1947
 History of Sulphonamides

1935: Scientist of Pasteur Institute of Paris conclude Azo linkage in Prontosil is

metabolically broken and the active entity sulphanilamide is generated.
 Sulphanilamide

 Sulfanilamide shown to have in vivo and in vitro activity

 Led to an explosion in the synthesis of sulfanilamide analogs

 Became the wonder drug of the 30s and early 40s

(referred to as sulfa drugs)

 A Little More History
• 1929-Alexander Fleming discovered Penicillin G
• 1941-Penicillin G shown to be successful antibacterial agent in
humans
– Leads to a decline in use of sulfa drugs
• However, sulfa drugs are still used for malaria, tuberculosis,
leprosy, meningitis, pneumonia, scarlet fever, plague,
respiratory, infections, and intestinal/urinary tract infections.

•The sulfonamide chemical moiety is also present in other drugs

including thiazide diuretics (including hydrochorothiazide),
sulfonylureas (including glipizide) and acetazolamide.
Nomenclature of Sulphonamides
• Sulphonamides are derivatives of para amino
benzene sulphonamide. The nitrogen atom of
– SO2NH2 is numbered as 1 and the – NH2
group as 4.
 Chemistry of Sulphonamides
• Structurally related to p-amino benzoic acid
(PABA).

A sulfonamide are derived from sulfonic acid (RSO2OH)group by replacing its

hydroxyl group with an amino group. Sulfonamides, also known as sulfa drugs.
Mechanism of Action
Mechanism of Action
 Mechanism of Action

• Folate is necessary for the bacterial cell to

synthesize nucleic acids (nucleic acids are
essential building blocks of DNA and RNA),
and in its absence cells will be unable to
divide.
• Hence the sulfonamide antibacterials exhibit a
bacteriostatic rather than bactericidal effect.
 Chemical Classification

1. N1 - substituted Sulphonamides: eg. Sulphacetamide , Sulphadiazine,

Sulphamethoxazole, Sulphamethizole, Sulphapyridine, Sulphisoxazole,
sulphamethazine

H2
H
Sulphapyridine.
Sulphisoxazole
Sulphamethizole

Sulphamethazine
 1.

1
2
Non-aniline Sulphonamides
Sulphamethizole
 Chemical Classification
2) N4 – substituted Sulphonamides (pro drugs):

eg. Prontosil,
Prontosil

Note: Pro-drugs of amines are occasionally prepared by incorporating them in to an azo linkage
. By the action of azo reductase the amino compounds are released in vivo.
 Chemical Classification
3) Both N1 and N4 - substituted
Sulphonamides: eg. Succinyl sulphathiazole,
Phthalyl sulphathiazole, Sulphasalazine

Succinyl sulphathiazole Phthalyl sulphathiazole

 Chemical Classification
Sulphasalazine: Amino Salicylic Acid Derivatives

Sulphasalazine
 Sulphasalazine
Sulphasalazineby the action of azo reductase releases the 5-amino salicylic acid

(5-ASA) and sulphapyridine. The generation of anti-inflammatory salicylic acid

prior to absorption prevents the systemic absorption of the agents and enhances

the concentration of it in active site (intestine). Therefore, sulphaslazineis mainly

used to treat inflammatory bowel syndrome due to the released 5-ASA.

Low absorption from GIT Low absorption from GIT

pKa=6.5
Due to low lipophilicity Mostly ionized at intestinal pH (6-7)
pKa=8.4 pKa=2.9
pKa=2.3

LogP =2.2
LogP =2.3 LogP =0.35
Amino salicylic acid
 Chemical Classification
4) Non-aniline Sulphonamides: eg. Mafenide
sodium

4-(AMINOMETHYL)BENZENESULFONAMIDE

Mafenide sodium
Sulpha Drugs
 Other Classification of Sulphonamides

1. On the basis of the site of action

(i) Sulphonamides for systemic infection: Sulphanilamide, Sulphadiazine, sulfisoxazole,

Sulphamethoxazole, sulphamethazine.

(ii) Sulphonamides for urinary tract infections: Sulphaisoxazole, Sulphathiazole, sulphamethizole .

(iii) Sulphonamides for intestinal infections: Phthalylsulphathiazole, Succinyl sulphathiazole,

Sulphasalazine, sulphaguanidine.

• (iv) Sulphonamides for local infections: Sulpahacetamide, Mafenide, Silver sulphadiazine.

• (v) Sulphonamides for dermatitis: Dapsone, Solapsone, Sulphapyridine

• (vi) Sulphonamides in combination: Trimethoprim with Sulphamethoxazole.

Other Classification of Sulphonamides

2. On the basis of the pharmacokinetic properties

(i) Poorly absorbed sulphonamides (locally acting sulphonamides): Sulphasalazine,

Phthalylsulphathiazole, Sulphaguanidine, Succinyl sulpha thiazole.

(ii) Rapidly absorbed and rapidly excreted (systemic sulphanamides):

Sulphamethoxazole, Sulphaisoxazole, Sulphadiazine, Sulphadimidine,
Sulphamethizole, Sulphacetamide.

(iii) Topically used sulphonamides: Sulphacetamide, Mafenide, Sulphathiazole,

Silver sulphadiazine.
 Other Classification of Sulphonamides

4. On the basis of the duration of action

(i) Extra-long-acting sulphonamides (half-life greater than 50 h): Sulphasalazine, Sulphalene.

(ii) Long-acting sulphonamides (half-life greater than 24 h): Sulphadoxine, Sulphadimethoxine,

Sulphamethoxy pyridazine, Sulphamethoxydiazine, Sulphaphenazole, Sulphamethoxine.

(iii) Intermediate-acting sulphonamides (half-life between 10–24 h): Sulphasomizole,

Sulphamethoxazole.

(iv) Short-acting sulphonamides (half-life less than 20 h): Sulphamethizole, sulphisoxazole.

(v) Injectable (soluble sulpha drugs): Sulphafurazole, Sulphadiazine, Sulphamethoxine

Synthesis of Sulphacetamide
Synthesis of Sulphamethoxazole
 Ionization of sulfonamides

•Sulfonamide group (SO2NH2) is unstable and get stabilized by losing a proton

which results in negative charge being stabilized by resonance with
sufonegroup.
•Therefore, the SO2NH2 group can be considered as HA acid similar to
carboxyls(-COOH), phenols (benzene-OH) and thiols(-SH).
•The R group in –SO2-NH-R affects the ionizabilityof NH. If R is electron with-
drawing group, the antibacterial activity and solubility of the drug is improved.
•Pyrimidine is more electron withdrawing than benzene and thiazole rings Eg :
Sulphadiazine and sulphamethazine.
•The lipid solubility influences the pharmacokinetic and antibacterial activity,
and so increases the half-life and antibacterial activity in vivo.
 Side Effects of Sulphonamides
• limitation of the sulfa drugs use:
– Sulfa allergic/hypersensitivity reactions.
– The formation of crystalluria.
– G.I T effects like nausea,vomiting ,anorexia,
diarrhoea.
– Effects on nervous system like head
ache,dizziness,depression, peripheral neuritis.
– They give toxic metabolites after the oxidation of
the aromatic amine.
 Crystalluria and pKa of sulfonamides

• Despite the good ability to treat infections, the sulfanilamide are associated with sever

renal damage due to crystallization in the kidneys

• The pKa of sulfonamidogroup (-SO2NH-) of sulfanilamide is around 10.4, therefore at urine

pH of 6 only 0.004% of sulfanilamide is ionized (water-soluble) to be excreted in urine.

• The precipitated sulfanilamide in urine lead to crystalluria.

• Sulpha drugs like are designed to have Pka close to urine pH (6) Eg: Sulphamethoxazole

(Pka =6.1) and sulphadiazine (Pka =6.5)

• Sodium bicarbonate was administered before each dose of sulfanilamide to improve

solubility and thus excretion in urine. Also increase the fluid intake
 Structure Activity Relationship (SAR)

• 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 and must be
directly attached to the ring.

• Any extra substitution will reduce activity.

• P-amino group is essential for activity and should be free (unsubstituted) except in the case of N-4 amino group could

be modified to be prodrugs, which are converted to free amino function in vivo. Eg: Prontosil, Pthalyl sulphathiazole.

• The substitution of amino group at ortho or meta position results in compounds devoid of antibacterial activity.
 Structure Activity Relationship (SAR)

• Sulphur atom should be directly linked to the benzene ring.

• Sulfonamide nitrogen must be either primary or secondary.

• 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.

 Structure Activity Relationship (SAR)

• On N-1-substituted sulphonamides, activity varies with the nature of the

substituent at the amido group. With substituents imparting electron-rich

characters to SO2 group, bacteriostatic activity increases. Heterocyclic substituents

lead to highly potent derivatives Eg: Sulphadiazine, Sulphamethoxazole,

Sulphamethizole , while sulphonamides, which contain a single benzene ring at N-

1 position, are considerably more toxic than heterocyclic ring analogues

 Structure Activity Relationship (SAR)

• 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.

• Meta-Sulphonamides bind to the basic centres 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.
 Trimethoprim

2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine

Pyrimethamine
 Trimethoprim
• Trimethoprim is a pyrimidine inhibitor of dihydrofolate
reductase, it is an antibacterial related to pyrimethamine.

• Belong to the class of antimetabolites.

• Trimethoprim is an antimetabolite which interference with folic

acid metabolism may cause a depression of hematopoiesis.

• Antibacterial action is potentiated by sulfonamides and the

trimethoprim-sulfamethoxazole combination (TMP/SMX) known
as co-trimoxazole, is the form most often used.
Mechanism of Action
 Synthesis of Trimethoprim

-C2H5OH
Sodium ethoxide
(Trimethoxy benzaldehyde)

Addition of NH2 to CN

Bond Reorganisation

Trimethoprim {2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine}
 Trimethoprim: Uses
• It is an antibiotic used to treat a variety of bacterial infections.
• - It is used for urinary tract infections, uncomplicated pyelonephritis
(with sulfamethoxazole), prophylaxis in females with recurrent cystitis and
mild acute prostatitis.
• Also used for the treatment of skin infections, travellers' diarrhoea,
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 orally or intravenously.
 +

Sulphamethoxazole
Trimethoprim
 Mechanism of Action

Synergestic Antimicrobial effect due to double sequential effects on the

bacterial metabolism

Sulphamethoxazole selected bcos of similar pharmacokinetic features with

trimethoprim.
 Cotrimoxazole : Uses
• Co-trimoxazole consists of one part
trimethoprim to five parts sulfamethoxazole.
• CO-trimoxazole is a drug combination with
broad-spectrum antibacterial activity against
both gram-positive and gram-negative
organisms.
• It is effective in the treatment of many
infections, including PNEUMOCYSTIS
PNEUMONIA in AIDS.
 Cotrimoxazole : Uses
• Used in the treatment of urinary,intestinal,
lower respiratory tract infections, typhoid
fever, chronic bronchitis, brucellocis and
endocarditis.
• Also effective for infections caused by
neisseria meningitidis and gonococci.
 Sulphones

R R’

• Sulfones belong to the class of organo sulfur

compounds.
• Sulfones are S, S-dioxides of ether and
represented by general structural formula
R-S(O)2-R’, where R and R’ are organic groups.
Dapsone
 Dapsone
• Dapsone, a sulfone active against a wide range
of bacteria but mainly employed for its actions
against mycobacterium leprae.
• Its mechanism of action is probably similar to
that of the sulfonamides which involves
inhibition of folic acid synthesis ( Antifolates)in
susceptible organisms by mimicing the action
of PABA
Dapsone
Structure Activity Relationship of Dapsone
Structure Activity Relationship of Dapsone
Dapsone
Dapsone: Uses

The principal drug in a

multidrug regimen
recommended by the
World Health
Organization for leprosy
 Dapsone: Uses
• Dapsone is a sulfone with anti-inflammatory
immunosuppressive properties as well as
antibacterial and antibiotic properties.
• As an anti-infective agent, it is also used for
treating malaria along with pyrimethamine.