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

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