The document discusses the history and discovery of sulphonamides, starting with Prontosil in 1935 by Gerhard Domagk, who later won a Nobel Prize for his work. It explains the mechanism of action of sulfanilamide as a competitive enzyme inhibitor and highlights the selective toxicity of sulfa drugs due to differences in folic acid metabolism between bacteria and humans. Additionally, it covers sulfonamide resistance and classification of various sulphonamides and their modern therapeutic applications.

1. SULPHONAMIDES
NISHU SINGLA
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICAL CHEMISTRY
ISF COLLEGE OF PHARMACY
WEBSITE: - WWW.ISFCP.ORG
EMAIL: NISHU131989@GMAIL.COM
ISF College of Pharmacy, Moga
Ghal Kalan,nGT Road, Moga- 142001, Punjab, INDIA
Internal Quality Assurance Cell - (IQAC)

2. HISTORY OF DRUG DISCOVERY 2
• In 1935, Gerhard Domagk discovered the first sulphonamide--prontosil rubrum. Four years
later he received the Noble Prize.
• Developed mouse model of sepsis with Streptococcus hemolyticus infection
• Lethal model with most mice dead in 24 hours
• Tested azo-dyes directly in this model.
• Others had shown some azo dyes to be active in vitro against a number of bacteria but not to
have any in vivo activity
N NH2N
NH2
Chrysoidin
N NH2N S
O
O
NH2
NH2
Prontosil Red

3. 3DISCOVERY OF SULFONAMIDES
-Prontosil “Red” - Azo-dye
• Pre-treatment of bacteria before infection, no effect, but subsequent administration to mice -
survival!
• In vivo activity but no in vitro activity!
N NH2N S
O
O
NH2
NH2
H2N S NH2
O
O
Prontosil Red Sulfanilamide
in vivo
• Pro-drug - active in vitro after reduction
• Sulfanilamide first shown active in vitro by Fourneau (1935)
• Specific for streptococci not other pathogenic bacteria
• Only tested in humans by necessity
• Nobel Prize in 1939 to Domagk

4. 4MECHANISM OF ACTION
WOODS (1940)
• Followed up on observation that bacterial extracts blocked bacteriostatic effects of
sulfa
• Suggested that sulfanilamide was a mimic for a bacterial metabolite and that it was
PABA
• First example of a competitive enzyme inhibitor as a drug (inhibitor and substrate)
H2N S NH2
O
O
Sulfanilamide
H2N C
O
O
-
p-aminobenzoic acid

5. 5Sulfanilamide Mechanism
N
N
N
H
N
O P O P O
-
O
O
-
O
O
-
H2N
OH
N
N
N
H
NH2N
OH
H
N C
O
O
-
H2 N C
O
O
-
DHFR
+
Dihydrofolic acid
Dihydropteroate Synthetase
Tetrahydro
folate
Purines
H2N S NH2
O
O
PABS derivative not
A substrate for DHFR
PABA
PABS
1 carbon transfer
DNA

6. 6WHY ARE SULFA DRUGS SELECTIVE ?
SELECTIVE TOXICITY
• Folic acid is a vitamin for humans - we don’t make it
• Therefore, no dihydropteroate synthetase
• Bacteria don’t have a folic uptake system since they make it
• Thus, a selective anti-bacterial agent!

7. 7SULPHONAMIDE RESISTANCE AND PRESENT USE
• Sulfonamide resistance mechanisms
• Increased synthesis of PABA
• Mutant enzyme - binds sulfonamides less well
• Decreased uptake of sulfa drugs
• Synergistic therapy
• Used today to treat P. Carinii pneumonia in HIV
Sulfa + DHFR inhibitor
H2N S NH
O
O
N
O
CH3
N
N
OCH3
OCH3
OCH3
H2N
NH2
sulfamethoxazole trimethoprim
DHFR inhibitor"Septra"

8. 8
CLASSIFICATION
1. Well absorbed short acting sulfonamide:
Sulfadiazine
Sulfamethimazole
Sulfadimidine
Sulfamethiazole
Sulfafurazole (Sulfaisoxazole)
Sulfosamidine
2. Well absorbed intermediate acting sulfonamide:
Sulfaphenazole
Sulfamethoxazole

9. 9
3. Well absorbed long acting sulfonamide:
Sulfadimethoxin
Sulfamethoxin
Sulfamethoxy diazine
Sulfamethoxy pyridazine
4. Well absorbed ultra long acting sulfonamide:
Sulfadoxine
Sulphalene
5. Sulfonamide employed for ophthalmic infection
Sulfacetamide
Sulfafurazole

10. 10
5. Sulfonamide employed for ophthalmic infection:
Sulfacetamide
Sulfafurazole
6. Sulfonamide employed for burn therapy:
Mefenide
Silver sulfadiazine
7. Sulfonamide employed for G.I.T. infection:
Succinyl sulfathiazole
Pthalyl sulfathiazole
Sulfaguanidine

11. 11
8. Folate reductase inhibitors:
Trimethoprim
9. Sulfones
Dapsone

12. 12
NH2 SO2 NH2
p-amino benzene sulfonamide
Sulfanilamide
NH2 SO2 NH C CH3
O
p-amino phenyl sulfonyl acetamide
N-acetyl-sulfanilamide
N-acetyl-p-aminobenzene sulfonamide

13. 13
NH2 SO2 NH
N
N
N-pyrimidin-2-yl sulfanilamide
2-p-amino benzene sulfonamido pyrimidine
NH2 SO2 N
N
N
.Ag
+
-

14. 14
NH2 SO2 NH
N
N
CH3
NH2 SO2 NH
N
N
CH3
CH3
Sulfamerazine
Sulfadimidine (Sulfamethazine)

15. 15
NH2 SO2 NH
N N
OCH 3
NH2 SO2 NH N
N
OCH 3
OCH 3Sulfodimethoxine
Sulfamethoxy pyridazine

16. 16
NH2 SO2 NH
O
N
CH3
NH2 SO2 NH N
O
CH3 CH3
Sulfaisoxazole (Sulfafurazole)
Sulfamethoxazole

17. 17
NH SO2 NH
N
S
COOH
C
O
NH SO2 NH
N
S
H2C COOH
H2C CO
sulfathiazole
Succinyl Sulfathiazole

18. 18
NH2 SO2 NH
N
Sulfapyridine
N SO2 NH
N
NOH
HOOC
Sulfasalazine

19. 19
Timethoprim
NH2 SO2 NH CO
Sulfabenzamide
N
N
NH2 CH2
CH3
CH3
CH3NH2

20. 20
Sulfomethizole
NH2 SO2 NH
N
S
N
CH3
NH2 SO2 NH
N
N
H3CO
Sulfalene

21. 21GENERAL METHOD OF SYNTHESIS
Conc. H 2SO4
Conc. HNO 3
NO2 Reduction
Sn/HCl
NH2
(CH3CO) 2O
NH C CH3
O
HSO 3Cl
NH C CH3
O
SO2 Cl
NH3
NH C CH3
O
SO2 NH2

22. 22
NH C CH3
O
SO2 NH2
N N
Cl NH2
NH C CH3
O
SO2 NH
N N
Cl
1. NaOH
2. Na/CH3OH
NH2 SO2 NH
N N
OCH 3
SYNTHESIS OF SULPHAMETHOXY PYRIDAZINE

23. 23SYNTHESIS OF TRIMETHOPRIM
CH3
CH3
CH3
CHO
H2C CH2 O
CN
C2H5
Ethanol
CH3
CH3
CH3
CH CH
CN
CH2 O C2H5
CH3
CH3
CH3
CH2 HC
CH(OC 2H5)2
CN
NH2 C NH2
NH
.HCl
CH3OH
N
N
NH2 CH2
CH3
CH3
CH3NH2