Sulfonamides

History:
• In 1932 Domagk reported that sulfamido-
chrysoidine (prontosil rubrum dye) was active in
experimental infections by b-hemolytic
streptococci.
• In 1935 a group of investigators at the Pasteur
institute in Paris reported that in vivo the azodye
linkage of sulfamido chrysoidine is reduced by
azoreductase, yielding sulfanilamide, and this is
the active moiety.
 H2N SO2-NH 2

H2N N N SO2-NH 2 Sulfanilamide

NH 2
Sulfamidochrysoidine H2N NH 2

NH 2

• Structure Activity relationship H2N SO2NHR

• Change in A A B C

• Free NH2 is essential for activity. Substitution by

another group such (NO2, NHOH or acetylation
(prodrugs) which will give free NH2 in vivo upon
reduction or hydrolysis or with acylated
compounds which will give in vivo upon
hydrolysis the free NH2 (e.g. sulfasalazine,
succinyl sulfathiazole and phthalyl sulfathiazole)
still retain its activity.
• Alkylation of NH2 gives inactive compounds.
• Removal of amino group or its substitution with
another group gives inactive compounds.
• Shifting of the NH2 group to m-position
(metanilide or to o- position (orthoanilide) gives
inactive compounds.
• Change in B
• Phenyl group is essential for activity,
replacement of this phenyl group with another
one such as naphthalene, anthracene, pyridine
or by another heterocyclic rings or saturation to
cyclohexyl or even its removal gives inactive
compounds.
• Substitution on benzene ring by halogen or
any other group will result in loss of activity.
• Change in C
• SO2 must be directly attached to benzene ring.
• NH2 which attached to SO2 (sulfanilamide) is still
active but weakly active. NH2 should be
substituted with R to give NHR because the NH2
derivative (sulfonamide) is the parent compound
but not used.
• R should be electron withdrawing group in order
to increase the acidity on N so lowering the pKa,
therefore the ionized form (responsible for the
activity) will increase and finally activity is
increased. Note that the intact molecule is only
responsible for penetration of cells.
• Best R is heterocyclic ring e.g.
sulfathiazole, sulfadimidine and
sulfadiazine and must be in a-position to
the hetero atom.
 Classes of sulfonamides
• a- Short-acting sulfonamides
Their half-lives vary from 4 to 7 hours
CH3
N N
N
H2N SO2 N CH3
H S H2N SO2 NH
Sulfamethizole N
Sulfamethazine CH3
4-Amino-N-(5-methyl-1,3,4-thiadiazole-2-yl)benzenesulfonamide.
or N1-(5-Methyl-1,3,4-thiadiazol-2-yl)sulfanilamide. 4-Amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide.
or 5-Methyl-2-sulfanilamido-1,3,4-thiadiazole. or N1-(4,6-Dimethyl-2-pyrimidinyl)sulfanilamide.
or 2-Sulfanilamido-4,6-dimethylpyrimidine.

N
H2N SO2 NH

Sulfapyridine
4-Amino-N-2-pyridiny)benzenesulfonamide.
or N1-2-pyridylsulfanilamide.
or 2-Sulfanilamidopyridine.
 b- Intermediate-acting
sulfonamides
• Their half-lives usually range from 10-12
hours
• They are useful in urinary tract and other
infections requiring prolonged treatment,
examples of this group are; sulfadiazine
and sulfamethoxazole.
 N
H2N SO2 NH H 2N SO2 NH
N CH3 N
Sulfamethoxazole O Sulfadiazine

4-Amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide. 4-Amino-N-(2-pyrimidinyl)benzenesulfonamide.
or N1-(5-methyl-3-isoxazolyl)sulfanilamide. or N1-(2-pyrimidinyl)sulfanilamide.
or 3-Sulfanilamido-5-methylisoxazole. or 2-Sulfanilamidopyrimidine.

• C- Long-acting sulfonamides
• They are rapidly absorbed and slowly
excreted, their half-lives are 35-40 hours,
slow excretion is related to an optimal
lipophilici (no longer used). E.g.
sulfadoxine.
 RHN SO2NR1R2

Name R R1 R2 pKa Solubility/ Plasma protein

1gm binding

N
Sulfadoxine H H N O slightly 90-95%
soluble
2- Intestinal sulfonamides O

• These drugs are used in intestinal

infections. They are insoluble in water,
they are poorly absorbed from the GIT so
it gives a local effect in the GIT. Bacterial
hydrolysis in the colon lumen will slowly
release the parent sulfonamide. Examples
are phthalyl sulfathiazole, succinyl
sulfathiazole, phthalyl sulfacetamide,
sulfaguanidine and sulfasalazine.
Examples are phthalyl sulfathiazole, succinyl
sulfathiazole, phthalyl sulfacetamide, sulfaguanidine and
sulfasalazine.
RHN SO2NR1R2

Sulfa R R1 R2 Solubility

CO-
Phthalyl sulfacetamide H COCH3 insoluble

COOH

CO- N

Phthalyl sulfathiazole H insoluble

S
COOH
N
CH2CO-
Succinyl Sulfathiazole H2C H insoluble
S
COOH
 N
Hydrolysis N
HO N N SO2NH HO NH2+H2N SO2NH

HOOC HOOC
m-aminosalicylic acid sulfapyridine

3-Urinary tract infections sulfonamides

These sulfonamides are used in urinary infections, because
they are rapidly absorbed but slowly excreted by the kidney
and thus reach high concentration there. Examples are
sulfadiazine, sulfamethoxine, sulfaisoxazole, sulfafurazole,
acetylsulfathiazole, sulfamethizole, sulfacetamide and
sulfaethidole. The preferred one is sulfacytine, sulfamethizole
and sulfaisoxazole, because they are safe and well tolerated
and have high solubility at normal pH of urine; therefore the risk
of crystalluria formation is low.
4- Ophthalmic sulfonamides
They are used in treatment of conjunctivitis, other superfacial ocular
infections, trachoma and chlamydial infections. Examples are
sulfacetamide and its sodium salts, as will as sulfaisoxazole diolamine.
These sulfa drugs must be water soluble.

RHN SO2NR1R2

Sulfa R R1 R2 pKa t 1/2 Solubility

O
Sulfacetamide sodium H Na C CH3 2.5 short soluble

H3C CH3

Sulfaisoxazole diolamine H diethanol-

amine N
O
 5- Sulfonamides for burn therapy
Mafenide Acetate (sulfamylon)

H2NH2C So2NH2

Mafenide

4-(Aminomethyl)benzenesulfonamide

It is not effective orally. It is currently employed alone

or with antibiotics in the treatment of slow healing,
infected wounds
6) In veterinary medicine, some sulfonamides
are exclusively used, such as,
nobrylsulfonamide, sulfabenz, sulfanilamide,
sulfaquinoxaline, and
sulfapyrazole.
O
NH N
S

O
N
H2N

Sulfaquinoxaline
Mode of Action of Sulfonamides (Bacteriostatic)
Due to the structure similarity between sulfonamides and p-
aminobenzoic acid (PABA). So sulfonamides compete with the PABA
for the dihydropteridine synthetase enzyme (DHP) so inhibit the
formation of dihydropteroic acid which is essential for the production of
tetrahydrofolic acid which is essential for bacterial growth.
Tetrahydrofolic acid is a cofactor in the synthesis of thymidine, purines
and finally DNA. Mammals also required folic acid as an essential
growth factor, but they get it from food intake. At physiological pH, folic
acid exists as a dianion, which can not cross the bacterial cell wall by
passive diffusion. For this reason these bacteria have to synthesize
folic acid de novo from PABA, and consequently, this process is
inhibited by sulfonamides, producing a bacteriostatic effect. i.e.
Sulfonamides act as a metabolite antagonist, its mechanism of action is
bacteriostatic in nature.

HOOC NH2 H2NO2S NH2

p-aminobenzoic acid Sulfonamide

Toxicity (side effects)
Crystalluria
•Most of sulfonamides are water insoluble, Sulfonamides often caused sever
kidney damage by forming crystals in the kidney.

Overcome of crystalluria

1) Increasing the pH of the urine by the use of NaHCO3

2) Increasing urine flow by water and fluid intake.

3) Using derivatives of sulfonamides that have lower pKa values, closer to
the pH of urine.
4) Use mixed sulfonamides (triple sulfa) because solubilities of
sulfonamides are independent, more of a mixture of sulfonamides can
stay in water solution at a particular pH than a single sulfonamide can.
Sulfasalazine (USP)

N
HO N N SO2NH

HOOC

5-[p-(2-pyridylsulfamoyl)phenylazo]salicylic acid.
Or 2-Hydroxy-5-[[(4-[2-benzoic acid.
It is insoluble in H2O, active only in vivo. Bacteria in the lower
bowel lead to hydrolysis to give sulfapyridine (which may be
absorbed lead to crystallurea) and 5-aminosalicylic acid which is
active and used in ulcerative colitis.
Silver sulfadiazine (Silvadene)

N
H2N SO2N
Ag N
Silver sulfadiazine

It is effective as topical antimicrobial agent, especially

against Pseudomonas species. It is very effective in
burn therapy.
Assay
1- Methods depend on free NH2
a) Diazotization
Direct titration against standard NaNO2 and the end point is determined either potentiometrically or
using starch iodide paper.
b) Colurimetrically
Diazotization with NaNO2 in the presence of HCl then coupling with Bratton Marchal reagent.
NH CH2CH2NH2
NH2 CH2CH2NH3

+ N N SO2NHR
. 2 Cl . Cl

Bratton Marchal reagent N N SO2NHR

Highly coloured compound measured

colourimetrically.
c) Spectrofluorometrically

H3C H3C
CH3 CH3
N N

- HCl
+H2N SO2NHR

SO2Cl SO2NH SO2NHR

Dansyl reagent

Fluorescent compound measured spectrophotometrically.

General methods for synthesis of sulfonamides

NH 2 NHCOCH3 NHCOCH3 NHCOCH3

(Ac)2O ClSO3H RNH2

- HCl
HCl,
SO2Cl H2O SO2NHR
NHCOCH3 NHCOCH3
NaOH,
NH 3 H2O
(Ac)2O NH 3Cl NH 2

SO2NHCOCH3 SO2NH 2

NaOH SO2NHR SO2NRNa

H
NH 2
NH 2
NaOH

SO2NHCOCH3
Sulfacetamide SO2NHR
Physicochemical properties of sulfa drugs
1.Amphoteric characters:

O
.. ..
H 2N S NH R
O
H OH
H OH
O
H 3N SO2NHR H 2N S N R
O

O
H2N S N R
O

O
H 2N S N R
O

Here sulfonamides contain weakly basic groups (NH2) so it can form salt
with acids. Also due to the presence of SO2 beside NH so it makes
inductive effect and makes the proton on NH slightly acidic
2- Solubility
• All sulfonamides are insoluble in water
except the sodium salt which are water
soluble.