SULPHONAMIDES

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: [email protected]   ISF College of Pharmacy, Moga Ghal Kalan,nGT Road, Moga- 142001, Punjab, INDIA Internal Quality Assurance Cell - (IQAC)

2. HISTORY OF DRUG DISCOVERY ISF CP 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

3. 3 ISF CP DISCOVERY 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! 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. 4 ISF CP MECHANISM 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)

5. 5 ISF CP Sulfanilamide Mechanism N N N H N O P O P O - O O - O O - H 2 N O H N N N H N H 2 N O H H N C O O - H 2 N C O O - D H F R + D i h y d r o f o l i c a c i d D i h y d r o p t e r o a t e S y n t h e t a s e T e t r a h y d r o f o l a t e P u r i n e s PABS derivative not A substrate for DHFR PABA PABS 1 carbon transfer DNA

6. 6 ISF CP WHY 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. 7 ISF CP SULPHONAMIDE 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

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

9. 9 ISF CP 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 ISF CP 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 Sulfasalazine

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

12. 12 ISF CP

13. 13 ISF CP

14. 14 ISF CP Sulfamerazine Sulfadimidine (Sulfamethazine)

15. 15 ISF CP Sulfodimethoxine Sulfamethoxy pyridazine

16. 16 ISF CP Sulfaisoxazole (Sulfafurazole) Sulfamethoxazole

17. 17 ISF CP sulfathiazole Succinyl Sulfathiazole

18. 18 ISF CP Sulfapyridine Sulfasalazine

19. 19 ISF CP Timethoprim Sulfabenzamide

20. 20 ISF CP Sulfomethizole Sulfalene

21. 21 ISF CP GENERAL METHOD OF SYNTHESIS

22. 22 ISF CP NaOH Na/CH 3 OH SYNTHESIS OF SULPHAMETHOXY PYRIDAZINE

23. 23 ISF CP SYNTHESIS OF TRIMETHOPRIM