1. S.SEETARAM SWAMY, M.Pharm.,
Asst. professor,
Dept. of Pharmaceutical Chemistry,
E-mail: seetaram.443@gmail.com
B. PHARM SEMESTER VI (3rd Year 2nd Sem.)

2. B. PHARM SEMESTER VI (3rd Year 2nd Sem.)
Topics Covered:
Historical development,
Chemistry, Classification,
Synthesis & SAR of
Sulfonamides,
Folate reductase inhibitors
& Sulfones
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3. 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.
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4. 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).
Chemical Modification of the sulphonamide structure has given rise
to several important group of drugs.
This group is also present in other non-antibacterial compounds like
Oral Hypoglycemic – Sulphonyl ureas
Diuretics – Thiazides (Furosemide)
Anti Mycobacterial - Sulphones
Glucoma -Acetazolamide
Chemistry of Sulphonamide
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5.  All sulfa are white crystalline powder except Sulfaquinoxaline
(yellow).
 Sulfa generally are weak organic acid, insoluble in water but much
more soluble in alkaline aqueous sol. than in neutral or acidic.
 The spectrum of all sulfonamides is generally the same.
Sulfonamide inhibit both Gram-positive & Gram negative bacteria,
Nocardia, Actinomyces spp, & some Protozoa as Coccidia &
Toxoplasma spp. & Streptococcus, Staphylococcus, Salmonella,
Pasteurella, & E. coli .
 Sulfa used to treat or prevent acute systemic or local infections.
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6. 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 (THFA).
Folic acid - synthesized from
PABA, pteridine and glutamate.
All sulfonamides are analogs of
PABA.
All sulfa drugs are bacteriostatic.
Mechanism of Sulfonamide
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8. SH2N
O
O
NH R
4
3 2
1
p-Amino group
Aromatic ring
Sulfanilamide group
N1
-Substitution group
SAR of Sulfonamide
Structure of Sulphonamides could be divided in to four parts:
1.) Para amino group
2.) Aromatic Ring
3.) Sulphonamide group
4.) N1-Substitution
1. Para Amino Group:
The para amino group is essential for the activity and must be
unsubstituted.
It should be always substituted on para position of aromatic ring other
wise anti bacterial activity is lost.
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9. 2. Aromatic Ring:
It is the minimal structural requirement for the antibacterial activity.
It should be always para substituted.
Replacement of Aromatic ring by other ring systems or the introduction of
additional substituents on it decreases or abolish activity.
3. Sulphonamide group:
Sulphonamide group along with aromatic ring is essential for the
antibacterial activity.
Sulphur atom should be directly linked to aromatic ring.
The amino & Sulphonyl groups on the benzene ring are essential & should
be in 1,4-position.
Exchange of the -SO2NH group by –CO-NH reduce the activity.
4. N1-Substitution:
Sulphonamide nitrogen should be primary or secondary.
R could be substituted with hydrogen, aromatic ring or heterocyclic ring.
Substitution of Aromatic Heterocyclic nuclei at N1 - yields highly potent
compounds.
N1 –Di substitution in general leads to inactive.
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10. 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
Classification According To Duration of Action
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11. 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
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12. Sulfonamide Structures

13. 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
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14. Synthesis of Sulfacetamide

15. Synthesis of Sulfasalazine

16. 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
Folate Reductase Inhibitors:
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17. Synthesis of Trimethoprim

18. Different Activities of Sulfonamide
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19.  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.
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20. 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,
Adverse Effects
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22. A sulfone is a chemical compound containing a sulfonyl
functional group attached to two carbon atoms. The central
hexavalent sulfur atom is double-bonded to each of two
oxygen atoms and has a single bond to each of two carbon
atoms, usually in two separate hydrocarbon substituents.
Dapsone
Dapsone (diamino diphenyl sulfone, DDS), It was discovered by German
chemists Fromm and Wittmann in 1908, Was not utilized as a treatment until
decades later.
Dapsone is used to treat dermatitis herpetiformis (a skin condition) and
leprosy. It is also used with other drugs to treat Hansen's disease.
Dapsone is commonly used in combination with rifampicin and clofazimine for
the treatment of leprosy
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23. Synthesis of Dapsone (Method-I)

24. Synthesis of Dapsone (Method-II)

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