Sulphonamides

Dr. Ejaz Ali

 Syllabus
General properties, chemistry, biological actions, structure activity
relationship and therapeutic applications of sulphonamides including;
1. Prontosil
2. Sulphanilamide
3. Sulphapyridine
4. Sulphadimidine
5. Sulfamethoxazole
6. Sulfadiazine
7. Sulfafurazole
 Objectives
• Introduction and history
• Chemistry
• Chemical synthesis
• Physicochemical properties
• Mechanism of action
• Structure activity relationship (SAR)
• Therapeutic uses
• Adverse effects
 Introduction and history

• The sulphonamides were the first effective chemotherapeutic agents used

systemically for the treatment of bacterial infectious diseases in human.

• Sulfonamides were discovered in 1930’s based on a hypothesis that synthetic

dyes might be taken up by certain bacteria in a manner analogous to the way
Gram staining works and will serve as selective poison to kill these bacterial
cells.
 Introduction and history
• Fritz Mietzsch and Joseph Klarer of the I. G. Farben industrie
laboratories systematically synthesized a series of azo dyes, each
containing the sulfonamide functional group, as potential
antimicrobial agents.

• Sulfonamide azo dyes were included in the test series because they
were readily synthesized and possessed superior staining properties.
 Introduction and history
• The Bayer pathologist, bacteriologist

and physician named Gerhard Domagk

evaluated the new azo dyes.

• In 1932, Domagk began to study a brilliant red dye, named Prontosil rubrum.

• Prontosil was found to protect against, and cure, streptococcal infections in

mice.

• However, Prontosil was found to be inactive in vitro antibacterial studies.

 Introduction and history
• In 1935, Trefouel and coinvestigators
performed a structure-activity study on the
sulfonamide azo dyes and concluded that the
azo linkage was reductively cleaved to release
the active antibacterial product, sulfanilamide.
• This finding was confirmed in 1937 when Fuller105 isolated free
sulfanilamide from the blood and urine of patients being treated with Prontosil
Chemistry of sulphonamides
Chemistry of sulphonamides
Therapy with sulphonamides
 Chemistry of sulphonamides
.
 Synthesis of sulfanilamide 1st method

.
Synthesis of sulfanilamide 2nd method
Synthesis of sulfanilamide 3rd method
Synthesis of sulfapyridine
Synthesis of sulfamethizole
Synthesis of sulfadimidine
Synthesis of sulfafurazole
 Chemistry of sulphonamides
.
 Ionization of sulfonamides
• The sulfonamide group, -SO2NH2 is unstable because
of lone pair of electrons present on S, O and N.
• The group tends to gain stability by losing a proton.
• The resulting negative charge is resonance stabilized.
• Hence, sulfonamides behave as acids.
• Their acid strength depends on their pKa values.
 Crystalluria by sulfonamides
• Sulfonamides are metabolized in the body by acetylation at N4.

• The resulting acetylated product is more insoluble and tends to crystallize

at normal physiological pH of urine (pH 6), all of the sulfanilamide is in the
relatively insoluble, nonionized form in the kidneys.

• The sulfanilamide coming out of solution in the urine and kidneys causes
crystalluria.
 Approaches to prevent crystalluria caused by sulfanilamide

1.Increasing the urine flow by taking plenty of water. The increased glomerular filtration rate

would minimize opportunity for seed crystals to form in the renal tubules.

2.Increasing the pH of the urine. The closer the pH of the urine is to 10.4, the more of the

highly water-soluble salt form will be present. Oral sodium bicarbonate is given to raise urine

pH.

3.Preparing derivatives of sulfanilamide that have lower pKa values, closer to the pH of the

urine. Electron-withdrawing, heterocyclic rings are attached to N 1 providing additional stability

for the salt form. Hence, the drugs donate a proton more easily, and the pKa values are lowered.
pH of urine and solubility of sulfonamides
 Mechanism of action of sulfonamides
• Folic acid acts as a coenzyme in enzyme catalyzed reactions of several
biosynthetic pathways that compose the one-carbon pool in animals, bacteria, and
plants.

• The reactions involving folic acid include; the enzyme thymidylate synthase,
which is required to form deoxythymidine monophosphate which is an important
precursor to DNA.

• Another key reaction is the generation of formyl groups for the biosynthesis of
formyl methionyl tRNA units, the primary building blocks in protein synthesis.
 Mechanism of action of sulfonamides
• Folate coenzymes are biosynthesized from dietary folic acid in humans and
other animals.

• However, microbes cannot assimilate folic acid from the growth medium or
from the host. The reasons may be that bacterial cell walls are impermeable to
folic acid.

• Bacteria and protozoa must biosynthesize them from PABA and pteridine
diphosphate.
Mechanism of action of sulfonamides
 Mechanism of action of sulfonamides
• The sulfonamides are structural analogs of PABA that competitively inhibit
the action of dihydropteroate synthase, preventing the addition of PABA to
pteridine diphosphate and blocking the net biosynthesis of folate coenzymes.
This action arrests bacterial growth and cell division.

• The competitive nature of the sulfonamides action means that the drugs do
no permanent damage to a microorganism, hence, they are bacteriostatic.

• The host’s immune system finally eradicates the bacteria.

Mechanism of action of sulfonamides
or
Dihydropteroate
synthase
 Spectrum of action of the sulfonamides
• Sulfonamides inhibit Gram-positive and Gram-negative bacteria, nocardia,
Chlamydia trachomatis, and some protozoa.

• Some enteric bacteria, such as E. coli and Klebsiella, Salmonella, Shigella,

and Enterobacter spp. are also inhibited.

• Many strains of once-susceptible species, including meningococci,

pneumococci, streptococci, staphylococci, and gonococci are now resistant.
Therapeutic uses
Sulphonamide used in combination
Therapy with sulphonamides
 Other uses of sulphonamide

There are also other commonly used drugs that are sulfonamides
including;

• The oral hypoglycemic drug tolbutamide.

• The diuretics furosemide and chlorthalidone.

Adverse drug reactions
Classification of sulfonamides
 Structure Activity Relationship (SAR)
.
 Structure Activity Relationship (SAR)

• Replacement of benzene ring with other ring systems or introduction of a

substituent on ring decreases or abolishes activity.

• The aromatic ring must be para-substituted.

• Both aromatic ring and the sulphonamide functional groups are required and
both must be directly attached to the aromatic ring.

• IF SO2 – NH2 IS REPLACE BY CO – NH THEN ANTI-BACTRIAL

ACTIVITY REDUCES.
 Structure Activity Relationship (SAR)
• The aniline (N4) amino group is very important for activity because any
modification of it other than to make prodrugs results in a loss of activity. For
example, all of the N4-acetylated metabolites of sulfonamide are inactive.

• Substitution at N1 usually produces different compounds with antimicrobial

spectrum.

• R is the only possible site that can be varied in sulphonamides.

• Various studies have shown that the active form of sulfonamide is the N1-
ionized salt.
 Structure Activity Relationship (SAR)
• Maximum activity seems to be exhibited by sulfonamides between pKa 6.6
and 7.4. This reflects, in part, the need for enough nonionized (i.e., more lipid
soluble) drug to be present at physiological pH to be able to pass through
bacterial cell walls.
Prontosil
Sulphanilamide
 Sulphapyridine

Sulphapyridine is a white, crystalline, odorless, and tasteless compound.

It is stable in air but slowly darkens on exposure to light.

It is soluble in water, alcohol, and acetone at 25°C.

It is freely soluble in dilute mineral acids and aqueous solutions of sodium

and potassium hydroxide.

The pKa of sulphapyridine is 8.4 and it's plasma half-life is 9 hours.

 Sulphapyridine

Sulfapyridine was the first drug to have a marked curative effect on pneumonia.

However, because of its relatively high toxicity, it has been replaced largely by

sulfadiazine and sulfamerazine for this indication.

It’s use has been limited only for dermatitis herpetiformis.

Several cases of kidney damage have resulted from acetyl sulfapyridine crystals

deposited in the kidneys.

It also causes severe nausea in most patients.

 Sulfadiazine

Soluble sulfadiazine is an anhydrous, white, colorless, crystalline powder soluble in

water (1:2) and slightly soluble in alcohol.

Its water solutions are alkaline (pH 9–10) and absorb carbon dioxide from the air,
with precipitation of sulfadiazine.

It is administered as a 5% solution in sterile water intravenously for patients

requiring an immediately high blood level of the sulfonamide.
 Silver Sulfadiazine

The silver salt of sulfadiazine applied in a water-miscible cream base has proved to be an
effective topical antimicrobial agent, especially against Pseudomonas spp. This is
particularly significant in burn therapy because pseudomonads are often responsible for
failures in therapy.

The salt is only slightly soluble and does not penetrate the cell wall but acts on the
external cell structure. Studies using radioactive silver have shown essentially no
absorption into body fluids. Sulfadiazine levels in the serum were about 0.5 to 2 mg/100
mL.
 Sulphadimidine
or
Sulphamethazine
• Sulfamethazine’s plasma half-life is 7 hours. This compound is similar in chemical
properties to sulfamerazine and sulfadiazine but does have greater water solubility
than either. Its pKa is 7.2.

• Because it is more soluble in acid urine than sulfamerazine is, the possibility of
kidney damage from use of the drug is decreased. The human body appears to handle
the drug unpredictably; hence, there is some disfavor to its use in this country except
in combination sulfa therapy (in trisulfapyrimidines, USP) and in veterinary medicine.
 Sulfamethoxazole

It occurs as a tasteless, odorless, almost white crystalline powder. The solubility of

sulfamethoxazole in the pH range of 5.5 to 7.4 is slightly lower than that of
sulfisoxazole but higher than that of sulfadiazine, sulfamerazine, or sulfamethazine.
Following oral administration, sulfamethoxazole is not absorbed as completely or as
rapidly as sulfisoxazole, and its peak blood level is only about 50% as high.
Sulfamethoxazole’s plasma half-life is 11 hours.
 Sulfafurazole
or
Sulfaisoxazole
This compound is a white, odorless, slightly bitter, crystalline powder. Its pKa is
5.0. At pH 6, this sulfonamide has a water solubility of 350 mg in 100 mL, and its
acetyl derivative has a solubility of 110 mg in 100 mL of water.

Sulfisoxazole’s plasma half-life is 6 hours. Sulfisoxazole possesses the action and

the uses of other sulfonamides and is used for infections involving sulfonamide-
sensitive bacteria. It is claimed to be effective in the treatment of Gram-negative
urinary infections.