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Sulphonamide

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Sulfonamide (also called sulphonamide, sulfa drugs or sulpha drugs) is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group.

Published in: Health & Medicine

Sulphonamide

  1. 1. Sulfonamide (Sulpha Drugs) S.SEETARAM SWAMY, M.Pharm., Asst. professor, Dept. of Pharmaceutical Chemistry, E-mail:seetaram.443@gmail.com
  2. 2. 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.
  3. 3. 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). This group is also present in other non-antibacterial compounds like -Sulphonureas -Benzothiazids -Furosemide -Acetazolamide They act as antimicrobial agents by inhibiting bacterial growth and activity and commonly called sulfa drugs. Chemistry of Sulfonamide
  4. 4. 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 (THF). Folic acid - synthesized from PABA, pteridine and glutamate. All sulfonamides are analogs of PABA. All sulfa drugs are bacteriostatic. Mechanism of Sulfonamide
  5. 5. SH2N O O NH R 4 3 2 1 p-Amino group Aromatic ring Sulfanilamide group N1 -Substitution group The amino & Sulphonyl groups on the benzene ring are essential & should be in 1,4-position Replacement of Aromatic ring by other ring systems or the introduction of additional substituents on it decreases or abolish activity. Exchange of the -SO2NH group by –CO-NH reduce the activity. Substitution of Aromatic Heterocyclic nuclei at N1 - yields highly potent compounds. N1 –Di substitution in general leads to inactive. SAR of Sulfonamide
  6. 6. 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 Mafenide Classification According To Duration of Action
  7. 7. 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
  8. 8. N H NS O O H2N Sulphapyridine N H N S O O N N COOH OH Sulfasalazine N N H NS O O H2N Sulfadiazine H NS O O H2N Sulfamethoxazole N O CH3 H NS O O H2N Sulfisoxazole O N CH3H3C Sulfonamide Structures
  9. 9. BACTERIAL SPECTRUM Staphylococcus pneumonia S. Pyogenes H. Influenzae H. Ducrey Nocardia Actinomycin
  10. 10. 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
  11. 11. NHCOCH3 SO2Cl NHCOCH3 SO2NH N N NH2 SO2NH N N H2O/H+ Sulphadiazine 2-amino pyridine N N H2N 4-acetamidobenzene - 1-sulfonyl chloride Hydrolysis Synthesis of Sulphadiazine
  12. 12. N H N S O O NH2 Sulphapyridine N H N S O O N N+ Cl- OH COOH N H N S O O N N COOH OH NaNO2/HCl Diazotisation Diazonium salt Salicyclic acid Coupling Sulfasalazine Synthesis of Sulfasalazine
  13. 13. 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
  14. 14. CH2OHH3CO H3CO H3CO H2 CH3CO H3CO H3CO H2N C NH NH2 Guanidine 3,4,5-Trimethoxy benzaldehyde H2C C C N N malononitrile C HC N NH2 H2 CH3CO H3CO H3CO N N NH2 H2N NH3 Trimethoprim Synthesis of Trimethoprim
  15. 15. Different Activities of Sulfonamide
  16. 16.  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.
  17. 17. 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, bone marrow depression and crysalluria Adverse Effects
  18. 18. Drugs are great ! But they will ruin your life !

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