Sulphonamides and Sulfone

This sulphonamide and Sulfone will be helpful to the students of Pharmacy specially in the subject of Medicinal Chemistry.

1. Sulphonamides and Sulfones Prepared By: Navdha Soni Asst. Professor L.J. Institute of Pharmacy Ahmedabad

2. Introduction Sulphonamide is a class of organic compounds that are amides of sulphonic acids, some of which are sulpha drugs and act as powerful inhibitors of bacterial activity. In 1935, it was discovered that a red dye called prontosil red had antibacterial properties in vivo (i.e. when given to laboratory animals). But no antibacterial effect was observed in vitro. Later it was discovered that prontosil red was metabolized by bacteria present in the small intestine of the test animal to give a product called sulphanilamide. Prontosil Red (Inactive) Sulphonamide (Active) Metabolic cleavage

3. The agent contains sulphonamide group(-SO2NH2) called para amino benzoic sulphonamide. Chemically sulpha drugs are amphoteric. They behave as weak organic acid with pKa 4.79 to 8.56. Though they are weakly soluble in water, their solubility is increased at alkaline pH. Sodium salts are however easily soluble in water. They are white crystalline powder. (- SO2NH 2 ) group present in sulphonamide is not essential but the important feature is that the sulphur is directly linked to the benzene ring. The para NH 2 is essential for antimicrobial activity of sulphonamide. Sulphonamide is the structural analogue of para amino benzoic acid(PABA). It inhibits bacterial folic acid synthesis(competitor of PABA). Chemistry of Sulphonamides

4. Folic acid is essential for the growth of bacteria. It is a precursor of purine synthesis and this purine is require for the synthesis of DNA & RNA. Para amino benzoic acid(PABA) is a precursor of folic acid and sulphonamide has structural similarity to PABA. In this bacteria, sulphonamide compete with the PABA for the enzyme folic acid synthetase and prevent the incorporation of PABA into folic acid, so folic acid is not synthesized. As a result bacteria are deprived of folic acid and are unable to multiply. Mechanism of Action P-Aminobenzoic Acid Dihydrofolate Tetrahydrofolate Nucleic acid synthesis Dihydropteroate Synthetase Dihydrofolate Reductase Sulfonamides Trimethoprim

5. Sulphonamides are active against Gram-positive and gram-negative bacteria. It is also active against Nocardia, chlamydia trachomatis, some protozoa. Antibacterial activity

6. Classification Depending Upon Duration Short acting sulphonamide Sulfamethiazole Sulfisoxazole

7. Classification Depending Upon Duration Intermediate acting sulphonamides Sulfamethoxazole Sulfamoxole

8. Classification Depending Upon Duration Long acting sulphonamides Sulfadimethoxine Sulfamethoxydiazine

9. Classification Depending Upon Duration Extra long acting sulphonamides Sulphasalazine Sulfalene

10. Other Sulphonamides Sulfamethazine Sulfapyridine Sulphacetamide

11. Sulphadiazine Mefenide acetate Other Sulphonamides

12. Structure activity relationship The major features of SAR of sulphonamides include: Sulphonamide skeleton is the minimum structural requirement for antibacterial activity. Sulphur atom should be directly linked to the benzene ring. In N 1 substituted sulphonamides, activity varies with the nature of the substituent at amido group. With substituents, impairing electron rich character of SO 2 group, bacteriostatic activity increase. Heterocyclic substituents leads to highly potent derivatives.

13. Structure activity relationship Sulphonamides that contain a single benzene ring at N 1 position are considerably more toxic than heterocyclic ring analogs . The free aromatic amino group sholreside para to the sulphonamido group. Its substituents at ortho and meta position results in compounds devoid of antibacterial activity. The presence of free amino group is very essential for the activity. Any substituents of amino group either results in prodrug nature or in the loss of activity. Ionized form of sulphonamide is active.( pKa - 6.6-7.4) Substituents of free sulphonic acid (-SO 3 H) group for sulphonamide function, destroys the activity but replacement by sulfinic acid group (-SO 2 H) and acetylation of N 4 position retains the activity.

14. Therapeutic uses Urinary tract infections. Upper respiratory tract infections. Nocardiosis. Sulfasalazine in IBD. Sulfacetamide in bacterial conjunctivitis & trachoma. Silver sulfadiazine for prevention of infection of. burn wounds.

15. Adverse effects Hypersensitivity reactions Crystalluria, hematuria , renal obstruction. Allergic nephritis Haemolytic anaemia, aplastic anaemia, thrombocytopenia. Kernicterus in new born

16. Trimethoprim – Sulfamethoxazole combination (Co-trimoxazole) Sulphamethoxazole Trimethoprim Mechanism of action: Sequential blocking of purine synthesis (synergism). Trimethoprim inhibits dihydrofolate reductase enzyme so inhibits tetrahydrofolic acid synthesis. The combination is bactericidal.

17. Clinical Uses Acute or Complicated or recurrent urinary tract Infections especially in females Upper respiratory tract infections Pneumocystis jiroveci pneumonia Toxoplasmosis Shigellosis Nocardiosis Typhoid fever Salmonella infections Prostatitis Community –acquired bacterial pneumonia

18. Adverse effects Megaloblastic anemia , leukopenia & granulocytopenia (can be prevented by administration of folic acid). All side effects associated with sulphonamides.

19. Sulfone Dapsone also known as  diaminodiphenyl sulfone (DDS) is an antibiotic commonly used in combination with  rifamoicin  and clofazimine for the treatment of   leprosy. Side effects may include a decrease in blood cells, red blood cell breakdown. Dapsone

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