Sulfonamides

(Synthetic Antimetabolites)

1-Discovery: (Serendipity)
The antibacterial activity of sulfonamides was first discovered by the observation
that azo-dye Prontosil caused remarkable cure of streptococcal infections of
mice. However, Prontosil was inactive on bacterial cultures. Prontosil`s inactivity
in vitro, but excellent activity in vivo, confirmed that sulfonamide portion of
Prontosil is the responsible for the observed antibacterial action.

2-General structure and nomenclature:

3- Mode of Action (bacteriostatic)

PABA is essential for synthesis of folic acid which is necessary for the growth of
bacteria – sulfonamides are chemically closed related to PABA – thus they
successfully compete with PABA in enzyme system (dihydropteroate synthase),
Gives slightly different chemical structure prevent bacteria from completing the
synthesis of folic acid. (Bacteriostatic)
This M.O.A is supported by the following observations: notes
1-PABA is added to a culture medium antagonize the effect of sulfonamide.
2-microorganisms which don't require folic acid are less sensitive to sulfonamide.
3-man cannot synthesis folic acid inside his body – so sulfonamides is selective
4-Resistance
Resistance may be developed by several mechanisms:
1) develop alternate synthetic routes for the synthesis of folic acid.
2) The bacterial cell wall becomes permeable to folic acid.
3) The organisms produce large amount of PABA.
5- Structure-activity relationship
-free amino group is essential for activity.
-if alkylated amino gp = no activity
-If replaced by an CH 3 or OCH 3 or OH or other
-Substitution on the aromatic ring = inactive
-if anther ring = inactive
functional gp, no activity is observed.
-If it is replaced by gp which can be converted in
vivo to free NH 3, activity is maintained in vivo but
not in vitro.(prodrug) Such as NO2, NO, NHOH,
N=N-, NHCOR
O O
-acylation with dicarboxylic acid like succinic acid
or phthalic acid yields sulfonamides that are not
absorbed in the small intestine but hydrolyzed in S R
the large intestine to free sulfonamides (intestinal N
sulfonamides)
H

H2N

-Substitution on the amidic nitrogen

with various groups results in a wide
must be para position fluctuation in activity.
-N1 disubstitution =inactive

6- General Method for the preparation of sulfonamides:

7- Metabolism,
1-acetylation of the aromatic amino group.

2-part conjugated with glucouronic acid.

3-part excreted unchanged.
- Most of N4-acetylated derivatives are less soluble than the unacetylated
compounds and have the tendency to crystallize in the renal tubules and
therefore causing kidney damage.
Several options for reducing the Crystalluria by:
1) Drinking large quantities of water during the period of sulfonamide therapy.
2) Combination of several sulfonamides reduces this feature e.g. mixed
sulfonamides or triple sulfa.
3) Raise the pH of the urine by giving alkalinizing substances e.g. sodium
bicarbonate. Forms Na salt-- water soluble

Disadvantage of sulfa: crystaluria, hypersensitivity, resistance

Mixed sulfonamides: Triple sulfa:
E.g. Sulfathiazole, sulfacetamide, and sulfabenzamide, administered
intravaginally in the treatment of bacterial vaginosis
Various combinations of sulfonamides used therapeutically the therapeutic
efficiency of the compounds is additive but the solubilities are independent of
each other
The advantages of the administration of this triple sulfa!!!
8- Classification of sulfonamides
1) Short-and long acting systemic sulfonamides.
2) Sulfonamides for ophthalmic infections.
3) Sulfonamides for burn therapy.
4) Sulfonamides for intestinal infection