The document discusses sulfonamide drugs, initiated by Gerhard Domagk's discovery of prontosil, which treats bacterial infections. It details their chemical structure, mechanisms of action as antimicrobial agents, and classifications based on duration and therapeutic use. Additionally, it highlights various sulfonamide derivatives, their historical applications, and associated adverse effects.

1. Sulfonamide
(Sulpha Drugs)
S.SEETARAM SWAMY, M.Pharm.,
Asst. professor,
Dept. of Pharmaceutical Chemistry,
E-mail:seetaram.443@gmail.com

2. Building on Ehrlich’s early work,
Gerhard Domagk, a medical doctor
employed by a German dye
manufacturer made a breakthrough
discovery by finding that a dye known
as prontosil, dosed orally, was effective
in curing life threatening streptococci
infections in humans. He made the
discovery in a desperate, but successful
attempt to save his daughter who was
dying of a streptococci infection.
PRONTOSIL
SH2N
O
O
NH2
SN
O
O
NH2N
NH2
H2N
NH2
H2N NH2
Prontosil
Sulfanilamide
Metabolisim
In-Vivo
German bacteriologist and pathologist who was
awarded the 1939 Nobel Prize for Physiology or
Medicine for his discovery (announced in 1932) of the
antibacterial effects of Prontosil, the first of the
sulfonamide drugs.

3. Recognized since 1932.
In clinical usage since 1935.
First compounds found to be effective antibacterial agents in safe dose
ranges.
Chemically, it is a molecule containing the sulfonamido (sulfanilamide,
SO2NH2) functional group attached to an aniline.
Structurally related to p-amino benzoic acid (PABA).
This group is also present in other non-antibacterial compounds like
-Sulphonureas
-Benzothiazids
-Furosemide
-Acetazolamide
They act as antimicrobial agents by inhibiting
bacterial growth and activity and commonly
called sulfa drugs.
Chemistry of Sulfonamide

4. Sulfonamide molecular structure
is similar to p-Amino benzoic acid
(PABA) which is needed in bacteria
organisms as a substrate of the
enzyme dihydro pteroate synthetase
for the synthesis of Tetra Hydro Folic
acid (THF).
Folic acid - synthesized from
PABA, pteridine and glutamate.
All sulfonamides are analogs of
PABA.
All sulfa drugs are bacteriostatic.
Mechanism of Sulfonamide

6. SH2N
O
O
NH R
4
3 2
1
p-Amino group
Aromatic ring
Sulfanilamide group
N1
-Substitution group
The amino & Sulphonyl groups on the benzene ring are essential & should
be in 1,4-position
Replacement of Aromatic ring by other ring systems or the introduction of
additional substituents on it decreases or abolish activity.
Exchange of the -SO2NH group by –CO-NH reduce the activity.
Substitution of Aromatic Heterocyclic nuclei at N1 - yields highly potent
compounds.
N1 –Di substitution in general leads to inactive.
SAR of Sulfonamide

7. Orally absorbable agents
Short acting (6-9hrs.)-
Sulfadiazine
Sulfacytine
Sulfamethizole
Sulfisoxazole
Intermediate acting (10-12hrs.)-
Sulfamethaxazole
Sulfamoxole
Long acting(7days)-
Sulfadoxine
Sulfamethopyrazine
Orally non absorbable agents
Sulfasalazine
Olsalazine
Topical agents
Silver sulfadiazine
Sulfacetamide
Mafenide
Classification According To Duration of Action

8. Topically applied sulfonamides
for eye infection-
Sulfacetamide(10%,20%&30%)
for skin infection-
Silver sulfadiazine
Mefanide acetate
GIT Infections
Succinyl sulfathaizole,
Phthalyl sulfathiazole,
Sulfaguanidine
Meningitis
Sulfadiazine,
Sulfadimidine
UTI Infections
Sulfioxazole,
Sulfamethopyrazine
Classification According To Therapeutic Use
Respiratory tract infections
Sulfaphenazine,
Cotrimoxazole
Leprosy
Dapsone,
Solapsone
Drugs for bowel disinfection
Sulfasalazine,
Pthalylsulfathiazole
Malaria
Sulfadoxine + Pyrimethamine
Nocardiosis
Sulfadiazine,
Sulfisoxazole

9. N
H
NS
O
O
H2N
Sulphapyridine
N
H
N S
O
O
N N
COOH
OH
Sulfasalazine
N
N
H
NS
O
O
H2N
Sulfadiazine
H
NS
O
O
H2N
Sulfamethoxazole
N
O CH3
H
NS
O
O
H2N
Sulfisoxazole
O
N
CH3H3C
Sulfonamide Structures

10. BACTERIAL SPECTRUM
Staphylococcus pneumonia
S. Pyogenes
H. Influenzae
H. Ducrey
Nocardia
Actinomycin

11. NHCOCH3
4-acetamidobenzene -
sulfonyl chloride
Benzene Nitrobenzene
NO2 NH2
NHCOCH3
SO2Cl
NHCOCH3
SO2NH2
NH2
SO2NH2
Aniline Acetanilide
4-acetamidobenzene -
sulfonamide
Sulfonamide
HNO3
H2SO4
Sn/HCl (CH3CO)2O
CH3COOH
ClSO3H
NH3
H2O/HCl
General Synthesis of Sulfonamides

12. NHCOCH3
SO2Cl
NHCOCH3
SO2NH
N
N
NH2
SO2NH
N
N
H2O/H+
Sulphadiazine
2-amino pyridine
N
N
H2N
4-acetamidobenzene -
1-sulfonyl chloride
Hydrolysis
Synthesis of Sulphadiazine

13. N
H
N S
O
O
NH2
Sulphapyridine
N
H
N S
O
O
N N+
Cl-
OH
COOH
N
H
N S
O
O
N N
COOH
OH
NaNO2/HCl
Diazotisation
Diazonium salt
Salicyclic acid
Coupling
Sulfasalazine
Synthesis of Sulfasalazine

14. COMBINATION OF : Fixed dose combination
SULPHAMETHAXAZOLE : TRIMETHOPRIM
5 : 1
400 mg - 800 mg : 80 mg - 160mg
SEQUENTIAL BLOCK.
Broad spectrum bactericidal combination.
Delays the development of bacterial resistance
SULPHADIAZINE : TRIMETHOPRIM
5 : 1
2000mg : 400mg
Trimethoprim is selective inhibitor of
bacterial DHFR
Individually they both are bacteriostatic but
the combination is bactericidal
CO-TRIMOXAZOLE
CO-TRIMAZINE
H2
CH3CO
H3CO
H3CO
N
N
NH2
H2N

15. CH2OHH3CO
H3CO
H3CO
H2
CH3CO
H3CO
H3CO
H2N C
NH
NH2
Guanidine
3,4,5-Trimethoxy
benzaldehyde
H2C
C
C
N
N
malononitrile
C
HC
N
NH2
H2
CH3CO
H3CO
H3CO
N
N
NH2
H2N
NH3
Trimethoprim
Synthesis of Trimethoprim

16. Different Activities of Sulfonamide

17.  Sulfapyridine was shown to be effective against pneumonia in 1938.
 Sulfacetamide found highly successful use in fighting urinary tract
infections starting in 1941.
 Succinoylsulfathiazole has been used against gastrointestinal tract
infections since 1942.
 Sulfathiazole was used very effectively during World War II to fight
infection in soldiers with battle wounds.
 Sulfanilamide itself, a potent antibiotic, never gained widespread use due
to its greater human toxicity versus its various derivatives.
 Acetazolamide sold under the trade name Diamox, is a carbonic
anhydrase inhibitor that is used to treat glaucoma, epileptic, seizures,
hypertension. Acetazolamide is available as a generic drug and is also
a diuretic.
 Sulfamethizole is an antibacterial sulfonamide available in tablet form
for oral administration. Its rapid renal clearance permit high
concentrations of active sulfamethizole to occur in the urinary tract,
making it especially applicable for the treatment of infections of this tract.

18. Produce mild-to-moderate nausea,
vomiting, headache and mental
depression.
Produce hypersensitivity reactions
(rashes, fever, eosinophilia).
Rarely cause Stevens-Johnson Syndrome,
erythema multiforme associated with
lesions of skin and mucous membranes.
Produce Kenicterus (bilirubun-induced
brain dysfunction) in neonates because of the
displacements of bilirubin form serum
albumin binding site.
Sever adverse effects includes hepatitis,
bone marrow depression and crysalluria
Adverse Effects

20. Drugs are
great ! But
they will
ruin your life !