PHARMACEUTICAL

CHEMISTRY IV 2023-2024

SULFONAMIDES
PHARMACEUTICAL-MEDICINAL CHEMISTRY

Dr. Efe Doğukan DİNCEL

SULPHANILAMIDE DERIVATIVES
SULFONAMIDES
(ANTIMETABOLITES)
(BACTERIAL FOLATE ANTAGONISTS)

O
R1HN S O
NHR2
The story of sulfonamides began with the discovery of the in vivo
antibacterial properties of prontocil / prontosil (red dye) (1935).
 PRONTOSIL
It was determined that Prontosil, which was inactive in vitro, was metabolized by bacteria in the small intestine of test

animals.

Prontosil is inactive in vitro.

Prontosil is a prodrug.

The metabolite with antibacterial effect is Sulfanilamide.

Sulfanilamide is the first synthetic antibacterial drug.

O O
N S O H2N S O
H2N N NH2 NH2

NH2
Sulfanilamide
Prontosil
 PRONTOSIL
Prontosil becomes effective in the body by converting it into Sulfanilamide, the main active compound, by the azo reductase

enzyme.

azo grubu
Azo group undergoes barsakta
bioreduction
NH2 biyoredüksiyona uğrar
in the intestine

H 2N N N SO2NH 2

4-((2,4-diaminophenyl)diazenyl)benzenesulfonamide
prontosil (ön ilaç)
Prontosil (Prodrug)

NH2

H 2N NH2 + H 2N SO2NH 2

Sülfanilamid (antibakteriyel)
Sulfanilamide (antibacterial)
Sulfanilamide derivatives have been developed that have a much
stronger antibacterial effect and less toxicity.

Sulfanilamide derivatives
O
R1HN S O
NHR2 . SO2NH2 Sulfonamide group

In the late 1940s, Penicillins began to replace these compounds due to their toxicity and the emergence of bacterial
strains resistant to these compounds.
Its usage areas are limited to resistant Gr(-) strains.
Today, Sulfanilamide derivatives are used in the treatment of urinary system and intestinal infections.
There are also ophthalmic (Sulfacetamide sodium) and topical (Silver sulfadiazine) uses.
 Structure-Activity Relationship of Sulfanilamide
Derivatives
Benzene
ring

O
Aromatic primary amino
R1HN S O Sulfonamide
group at para position
NHR2
-The benzene ring and sulfonamide group are required for biological activity.
-The para amino group is required and must be unsubstituted (R1=H).
-R1 / R2 = acyl groups must be metabolized in vivo into the active compound. For this reason, amide derivatives are used as
prodrugs.
-The sulfonamide nitrogen must carry H with a pKa similar to that of PABA (about 6.5).
-R2 = aromatic or heteroaromatic rings significantly increase biological activity, improve pharmacokinetic properties and
reduce toxicity.
-The sulfonamide group must be attached to the ring through sulfur.
-Water-soluble alkali salts can be made from sulfonamide nitrogen.
 -The major biotransformation of sulfonamides is acetylation from N4.

Major metabolite

Acetylated derivatives are excreted by the kidneys. Most of the sulfonamide derivatives are poorly soluble in water.
Acetylated derivatives have poorer solubility. Therefore, they crystallized (crystalluria) while being excreted from the
kidneys and cause kidney damage.

With the N1 hetero ring substitution, the acidity of the drug is increased (pKa decreases). Increasing acidity increases
the ionization of the drug at physiological pH (pH = 7.4), making it more soluble. Similarly, the solubility of its
metabolite also increases. From this point forward, the crystallization in the kidneys and toxicity are reduced.
 O O
H2N S O N HN S O N
N-Acetylation
HN Me C HN
S O S

Sulfathiazole N-Acetylsulfathiazole

pKa=7.25

In acetylated derivatives, the hydrophobic character increased and the solubility in water decreased.

While excreted by the kidneys, they crystallized (crystalluria) and cause kidney damage.
 Sulfonamides with low toxicity
O O
H2N S O N H2N S O N
HN HN
S N
Sulfathiazole Sulfadiazine

pKa=7.25 pKa=6.48

The thiazole ring is replaced by the pyrimidine ring.

The pyrimidine ring attracts more electrons.
The sulfonamide NH proton is more acidic and ionized.
Sulfadiazine and its metabolite are more soluble in water.
Toxicity decreases, effectiveness increases.

O
O pKa 6.48
H2 N S O N
H2N S O N
N
HN
N
N
ionized
 O
- H+ O
H2N S NHR
H2N S NR
O O
noniyonize
non-ionized form
form iyonize
ionized form
form
O.

H2N S NR

iyonize form
ionized form

Aromatic or heteroaromatic structures can affect the solubility of sulfonamides; the toxicity of the compound ionized at
physiological pH decreases and its effectiveness increases.

Ionization also causes an increase in the activity of the drug. However, it must have sufficient lipid solubility to enter
bacteria. By bringing hetero rings to N1, the balance between the non-ionized form and the ionized form is achieved.
Acidity (polarity) and lipid solubility (lipophilicity) are maintained at a certain level.
 Sulfanilamide-derived antibacterials

Sulfanilamide
4-aminobenzenesulfonamide

Sulfacetamide
short

N1-acetylsulfanilamide

Sulfathiazole
N1-(2-thiazololyl)sulfanilamide
short
Sulfisoxazole
N1-(3,4-dimethyl-5-isoxazolyl)sulfanilamide

Sulfamethoxazole
medium

N1-(5-methyl-3-isoxazolyl)sulfanilamide

Sulfadiazine
N1-(2-pyrimidinyl)sulfanilamide

Sulfadimethoxine
long

N1-(2,6-dimethoxy-4-pyrimidinyl)sulfanilamide

Sulfamethoxypyridazine
N1-(6-methoxy-3-pyridazinyl)sulfanilamide
 Sulfanilamide and other sulfonamide
derivatives
• They are first effective antibacterial drugs.
• They act by mimicking p-aminobenzoic acid (PABA) in the structure of folic acid due to its
structural similarities. They are antimetabolites of PABA.
• Unlike p-Aminobenzoic acid (PABA), they inhibit the growth of bacteria.

NH2 NH2

SO2NHR COOH

Sulfonamides PABA
Sulfonamides PABA
Antimetabolite Metabolite
 Binding to dihydropteorate synthetase enzyme

O O
H2 N C H2 N S NR
O O
H vdw Ionic H vdw
bond Ionic
bond bond bond bond bond

p-Amino benzoic acid Sulfonamides

By binding to the dihydropteorate synthetase enzyme instead of PABA, sulfonamides competitively inhibit the
synthesis of folic acid required for bacterial cell growth, thus stopping cell proliferation and creating a bacteriostatic
effect.
Folic acid is essential for bacterial growth.
Folic acid synthesis is inhibited by binding sulfonamides to the pteridine
derivative instead of PABA in the structure of folic acid.
Bacteria can not multiply and the infections disappears.

Glutamic acid Pteridine derivative

PABA
The action of sulfonamides results from two metabolic differences between
mammalian and bacterial cells:

Higher living creatures obtain folic acid through nutrition.

However, bacteria lack a carrier protein that would allow folic acid to pass
outside the cell.

The bacterium has a sensitive enzyme (dihydropteorate synthetase) that is

not found in mammalian cells.

Due to these differences, higher organisms are not affected by sulfonamides.

It is not suitable for use in patients with low immune systems.

 Bacterial Folic Acid Synthesis

Pteridine
derivative

PABA

Glutamic
acid
PABA

Glutamic acid

Folic acid
 Sulfonamides that bind to
pteridine derivatives instead
of PABA inhibit folic acid
Sulfonamides PABA synthesis at this stage. Since
there is no free carboxyl
group in this structure,
glutamic acid can not bind to
the structure.
 Bacterial folic acid synthesis
Bakteriyel Folik
Bacterial folic Asit
acid Sentezi
synthesis
1
8 N NH
N NH H2N
H2N
ATP
6 O O
3 N N
N CH2OH
4 N CH2 O P O P OH
5
OH
OH OH OH
2-amino-4-hidroksi-6-hidroksi
2-Amino-4-hydroxyl-6-
metil- 7,8-dihidropteridin
hydroxymethyl-7,8- SO2NH2
dihydropteridine
NH
dihidropteroat
Dihydropteorate N NH
H2N
COOH
sentetaz
synthetase
N
N CH2 NH COOH
H2N COOH
OH HC NH2
PABA
7,8-dihidropteroik
7,8 asit
Dihydropteroic acid CH2

sülfanilamid
sulfanilamide CH2

PAS,Dapsone
PAS, Dapson COOH

glutamik
Glutamicasit
acid
 Bacterial folic acid synthesis
Sulfanilamide and its derivatives, PAS with tuberculostatic effect and
Dapsone effective against leprosy, bind to the active site of the
enzyme called dihydropteorate synthetase by competing with PABA
and inhibit the formation of 7,8-dihydropteroic acid and therefore the
synthesis of folic acid.
 H
N N O
H2 N COOH dihydropteorate
NH CH dihidrofolat redüktaz
synthetase
N CH2
N CH2 NH CH2
OH COOH
Trimetoprim
Trimethoprim
dihidrofolik asit
Dihydropholic acid
Primetamin
Pyrimethamine
Tetroksoprim
Tetroxoprim
H
N N O
H2 N COOH
NH CH
CH2 DNA + RNA
N CH
N CH2 NH CH2
H COOH
OH

tetrahidrofolik asit
Tetrahydrofolic acid
-Trimethoprim, Pyrimethamine and Tetroxoprim inhibit dihydrofolate
reductase, inhibiting the formation of tetrahydrofolic acid from
dihydrofolic acid, thus inhibiting DNA and RNA synthesis.
-They are used together with some sulfonamide derivatives.
-With these combinations, folic acid synthesis is blocked at two
different points.
-These combinations significantly delay the emergence of resistance.
SÜLFANİLAMİD
SULFANILAMIDE

4 1
H2N SO2NH 2 4-Aminobenzensülfonamid
4-aminobenzene sulfonamide

Sentezi:
Synthesis NO2 NH2 HN C CH3

H2 CH3CO)2O ClSO2OH

-H2O

H
O
O
HN C CH3 NH2
HN C CH3

NH3 hydrolysis
hidroliz

seyreltik
Diluted acidasit
or
alkali
veya alkali
SO2Cl SO2NH2
SO2NH2
SULFANILAMIDE
sülfanilamid
Sülfanilamid türevlerinin derivatives
Synthesis of sulfanilamide sentezi:

HN C CH3

SO2Cl

RNH2

O
NH2
HN C CH3

hidroliz
hydrolysis

seyreltik asit
Diluted acid or
alkali
veya alkali

SO2NHR
SO2NHR
Sülfanilamid türevleri
sulfanilamide derivatives
 SÜLFİSOKSAZOL SENTEZİ:
Synthesis of Sulfisoxazole

CH3 CH3 CH3 CH3

C 2H5ONa -H2O
CH2 + C O C 2H5 HC C

N C O
N C O

propionitril
propionitrile asetik
acetic asit
acidetil esteri
ethyl ester HO NH2

H3C CH3 H3C CH3 H3C C NH SO2Cl

O
N N
HN O H2 N O

H3C CH3
H 3C CH3
H30+
N
N H2N SO2NH. O
H3C C NH SO2NH. O
O
SÜLFİSOKSAZOL
Sulfioxazole

ÜrinerUsed in urinary
sistem tract infections
infeksiyonlarında kullanılır.
 Acetyl Sulfisoxazole (Gantrisin, Gantrisinin)
N CH3
O
O
H2N S N CH3

O COCH 3

N1-Acetylsulfisoxazole
It is the prodrug of Sulfisoxazole.
It is hydrolyzed to active Sulfisoxazole in the intestine.
It is used in combination with Erythromycin ethyl succinate (EES) to
treat otitis media.
 Sulfadiazine (Adiazine, sulfadiazine)
N
H2 N SO2NH
N

It is used in the treatment of toxoplasma in combination with Pyrimethamine.

Ag
N
SULFADİAZİN
SulfadiazineGÜMÜŞ
Silver
H2 N SO2N
N

Topik
It is usedolarak
topicallyyanık yaralarının
to protect infeksiyondan
burn wounds from infections,korunmasında, Gr(-)
in the treatment of burnsve Gr(+)
infected
mikroorganizmalar ve funguslarla
with Gr(-) and Gr(+) microorganisms infekte
and fungi, and forolan yanıkların
the prophylaxis tedavisinde,
and treatment of
diğer cilt lezyon ve yaralarının profilaksi
other skin vewounds.
lesions and tedavisinde kullanılır.

Sülfadiazin emilirken,isgümüş
While the Sulfadiazine absorbed,yavaş yavaş
the silver serbestlenerek
is gradually absorplanır
released and absorbed, thus ve
çift etkili tedavi sağlanır.
providing double-effect treatment.
 2-aminopyrimidine synthesis
H O H 3C O O CH
C C2H5 + C C2H5
C 2H5ONa CH2
O O
H5 C2 O C O

formil asetik
Formyl asitacid
acetic etil ethyl
esteriester
NH2

H2N C

NH
C 2H5ONa
guanidin
guanidine
N N
POCI3
H 2N H2N
N N
OH O

N
N o
Zn / OH -
H 2N
H2N
N
N
Cl
 N N
H2N SO2NH. OCH3
SÜLFAMETOKSİPİRİDAZİN SENTEZİ:
Synthesis of Sulfamethoxypyridazine

H2 N NH2 H H
-2 C2H5OH N N N N
H5 C2 O OC2H5 O O HO OH
O O

maleik acid
Maleic asit diethyl
dietil esteri
ester

H3C C NH SO2NH2
POCl3 N N
O
Cl Cl
veya
or PCl5 K2CO3

HOOC COOH HOOC

COOH

maleik asit
Maleic acid fumarik
Fumaricasit
acid
 N N CH3ONa
H3C C NH SO2NH. Cl
CH3OH
O

N N H3O+
H3C C NH SO2NH. OCH3
O

N N
H2N SO2NH. OCH3 SÜLFAMETOKSİPİRİDAZİN
Synthesis of Sulfamethoxypyridazine

It is used in urinary tract infections.

 Sulfonamides used in gastrointestinal infections
• In these drugs, hydrophilic groups are attached to free amino group
to increase water solubility.

• Due to the presence of hydrophilic groups in the weakly alkaline

environment of the gastrointestinal tract, these prodrugs are ionized
and poorly absorbed.

• Therefore, they reach high concentrations in the colon lumen. They

act by releasing the active sulfanilamide derivative as a result of
bacterial enzymatic hydrolysis in the colon lumen.
 FTALİLSÜLFATİYAZOL (ÖN İLAÇ)
PHTHALYL SULFATHIAZOLE

N
CONH SO 2NH N4-(Ftalil)-N 1
-(2-tiyazolil)
N4-Phthalyl-N1-(2-

S thiazolyl)sulfanilamide
sulfanilamid
COOH

N
COOH
+ H2N SO 2NH
S
COOH

Ftalik
Phthalic asit
acid Sülfatiyazol
Sulfathiazole

Oral yolla alındığında barsaklardan hemen hemen hiç absorplanmaz.

When taken orally, it is almost not absorbed from the intestines. Here, it is metabolized to sulfathiazole and phtalic
Burada sülfatiyazol ve ftalik aside metabolize olur. Ana bileşik
acid. It acts by releasing the main compound. It is a medicine used for intestinal infections.
serbestlenerek etki eder. Barsak infeksiyonlarında seçilen bir ilaçtır.
 SÜLFATİYAZOL ve FTALİL SÜLFATİYAZOL
SYNTHESIS OF SULFATHIAZOLE AND PHTHALYL ELDESİ:
SULFATHIAZOLE
N

H3 C C NH SO2Cl +
H2N 2-aminotiyazol
2-aminothiazole
O S

piridin
pyridine

N N
hydrolysis
hidroliz
H3 C C NH SO2NH H2N SO2NH
S S
O

SÜLFATİYAZOL
Sulfathiazole
O

COOH
O
N
ftalik asit acid
Phthalic anhidriti
anhydride
C NH SO2NH
S
O

FTALİL SÜLFATİYAZOL
Phthalyl sulfathiazole
 2-Aminothiazole synthesis
NH HO
-H2O N
CH
H2 N C +
CH -HCl
SH H 2N S
Cl

O
NH2 CH
H2N C CH2
S Cl

-kloroasetaldehid
α-chloroacetaldehyde
thiourea
SULFASALAZİN (ön ilaç)
Sulfasalazine (Prodrug)

5 1 4 2
N N SO 2NH
2 1 N
HO 1
COOH
5-[4-(2-piridinilsulfamoil)fenilazo]salisilik asid
2-hydroxyl-5-((4-N-(pyridin-2-yl)sulfamoyl)phenyl)diazenyl)benzoic acid

Barsaklarda
EscherichiaE.coli
coli azo reduction
in the intestines
azo redüksiyonu

NH2

+ H2N SO2NH
HO N
COOH
sülfapiridin (antibakteriyel)
Sulfapyridine
(antibacterial)
mesalazin=
Mesalazine =5-aminosalisilik
5-amino salicylicasit
acid
(anti-inflammatory)
(antienflamatuar)

Çift yönden etkili olan which

Sulfasalazine, sülfasalazin
is duallyülseratif
effective,kolit tedavisinde
is used kullanılır.
in the treatment of ulcerative colitis.
Sülfasalazin Sentezi:
Sulfasalazine synthesis
O O
NH2
HN C CH3 HN C CH3

hidroliz
+ H2 N
N
2-aminopiridin
2-amino pyridine SO2 NH
SO2Cl SO2 NH
N
N
Sülfapiridin
sulfapyridine

OH OH
+
N N
COOH
N N COOH
NaNO2 / H+

0-15 0C OH- SÜLFASALAZİN

Sulfasalazine
SO2 NH

N
SO2 NH

N
 Other Antimetabolites (Diaminopyrimidines)
dihidrofolat redüktaz
Dihydrofolate reductase
dihidrofolik asit
Dihydrofolic acid tetrahidrofolik asit
Tetrahydrofolic acid DNA + RNA

Trimetoprim
Trimethoprim

Primetamin
Pyrimethamine

Tetroksoprim
Tetroxoprim

Dihydropholate reductase is found in mammalian cells as well as in bacterial cells, and the same reaction occurs here too.

The reason why these compounds do not affect mammalian cells is that they can differentiate bacterial and mammalian
enzymes. Mutations over millions of years have caused significant differences between the two enzymes. Therefore, these
compounds recognize and inhibit the bacterial enzyme.
 Diaminopyrimidine
OCH3
1 3
N
5
2 1 4
H2N CH2 OCH3 TRİMETOPRİM
Trimethoprim

4 5
3N
NH2 OCH3

2,4-Diamino-5-(3,4,5-trimetoksibenzil)pirimidin
2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine

Trimetoprim dihidrofolat redüktazı inhibe ederek bakteriyel folik asit

sentezini
Trimethopriminhibe eder.folicDNA
inhibits bacterial sentezi
acid synthesis ve dihydrofolate
by inhibiting hücre büyümesi inhibe andolur.
reductase. DNA synthesis cell
growth are inhibited. Trimethoprim is both antimalarial and antibacterial.
Trimetoprim hem antimalaryal, hem de antibakteriyel etkilidir.
 The following mixtures are used for antibacterial treatment.

Sulfamethoxazole + Trimethoprim = Co-trimoxazole

Sulfadiazine + Trimethoprim = Co-trimazine

With these combinations, a synergistic effect is achieved by blocking folic acid synthesis from two different
points.

Co-trimoxazole (Bactrim, Kemoprim, Metoprim, Trimoks)

It is used in urinary system and gastrointestinal system infections.

 Trimethoprim synthesis
H3CO C N H3CO C N

CH2 CH3ONa H3CO CH C

H3CO CH O +

H3CO H2C H3CO H2C

OCH3 OCH3

NH
H3CO C N
C
H3CO CH2 C H2N NH2

H3CO CH OCH3
guanidine

HN H H3CO H2N
H3CO N
N
H3CO CH2 NH2
H3CO CH2 NH2
N
N
H3CO
H3CO
 Tetroxoprim
NH2 O CH3
N
H 2N CH2 O CH2 CH2 O CH3
N
O CH3

2,4-Diamino-5-[3,5-dimethoxy-4-(2-methoxyethoxy)benzyl]pyrimidine

Sulfadiazine + Tetroxoprim = Co-tetroxazine

It is especially used in urinary and respiratory system infections.

 Pyrimethamine
C 2H 5
1
N
5
2
H2N Cl
4
3N
NH2

2,4-Diamino-5-(4-klorofenil)-6-etilpirimidin
2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine

Pyimethamine inhibits bacterial folic acid synthesis by inhibiting dihydrofolate reductase. It is both antimalarial and anti-
Bacterial. It is used in combination with sulfanilamide derivatives in the treatment of toxoplasmosis and malaria.

Sulfadiazine / Pyrimethamine.