Historical development, classification, synthesis and SAR of sulfonamides, folate reductase inhibitors and sulfones
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Sulfonamides, Sulfones, Historical development, chemistry, classification and SAR of Sulfonamides: Sulphamethizole, Sulfisoxazole, Sulphamethizine, Sulfacetamide*, Sulphapyridine, Sulfamethoxaole*, Sulphadiazine, Mefenide acetate, Sulfasalazine. Folate reductase inhibitors, Trimethoprim, Cotrimoxazole, Sulfones, Dapsone
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Historical development, classification, synthesis and SAR of sulfonamides, folate reductase inhibitors and sulfones
- 1. S.SEETARAM SWAMY, M.Pharm., Asst. professor, Dept. of Pharmaceutical Chemistry, E-mail: seetaram.443@gmail.com B. PHARM SEMESTER VI (3rd Year 2nd Sem.)
- 2. B. PHARM SEMESTER VI (3rd Year 2nd Sem.) Topics Covered: Historical development, Chemistry, Classification, Synthesis & SAR of Sulfonamides, Folate reductase inhibitors & Sulfones More Updates Visit @ www.pharmawisdom.co.in copy right @ www.pharmawisdom.co.in
- 3. 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. copy right @ www.pharmawisdom.co.in
- 4. 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). Chemical Modification of the sulphonamide structure has given rise to several important group of drugs. This group is also present in other non-antibacterial compounds like Oral Hypoglycemic – Sulphonyl ureas Diuretics – Thiazides (Furosemide) Anti Mycobacterial - Sulphones Glucoma -Acetazolamide Chemistry of Sulphonamide copy right @ www.pharmawisdom.co.in
- 5. All sulfa are white crystalline powder except Sulfaquinoxaline (yellow). Sulfa generally are weak organic acid, insoluble in water but much more soluble in alkaline aqueous sol. than in neutral or acidic. The spectrum of all sulfonamides is generally the same. Sulfonamide inhibit both Gram-positive & Gram negative bacteria, Nocardia, Actinomyces spp, & some Protozoa as Coccidia & Toxoplasma spp. & Streptococcus, Staphylococcus, Salmonella, Pasteurella, & E. coli . Sulfa used to treat or prevent acute systemic or local infections. copy right @ www.pharmawisdom.co.in
- 6. 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 (THFA). Folic acid - synthesized from PABA, pteridine and glutamate. All sulfonamides are analogs of PABA. All sulfa drugs are bacteriostatic. Mechanism of Sulfonamide copy right @ www.pharmawisdom.co.in
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- 8. SH2N O O NH R 4 3 2 1 p-Amino group Aromatic ring Sulfanilamide group N1 -Substitution group SAR of Sulfonamide Structure of Sulphonamides could be divided in to four parts: 1.) Para amino group 2.) Aromatic Ring 3.) Sulphonamide group 4.) N1-Substitution 1. Para Amino Group: The para amino group is essential for the activity and must be unsubstituted. It should be always substituted on para position of aromatic ring other wise anti bacterial activity is lost. copy right @ www.pharmawisdom.co.in
- 9. 2. Aromatic Ring: It is the minimal structural requirement for the antibacterial activity. It should be always para substituted. Replacement of Aromatic ring by other ring systems or the introduction of additional substituents on it decreases or abolish activity. 3. Sulphonamide group: Sulphonamide group along with aromatic ring is essential for the antibacterial activity. Sulphur atom should be directly linked to aromatic ring. The amino & Sulphonyl groups on the benzene ring are essential & should be in 1,4-position. Exchange of the -SO2NH group by –CO-NH reduce the activity. 4. N1-Substitution: Sulphonamide nitrogen should be primary or secondary. R could be substituted with hydrogen, aromatic ring or heterocyclic ring. Substitution of Aromatic Heterocyclic nuclei at N1 - yields highly potent compounds. N1 –Di substitution in general leads to inactive. copy right @ www.pharmawisdom.co.in
- 10. 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 Classification According To Duration of Action copy right @ www.pharmawisdom.co.in
- 11. 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 copy right @ www.pharmawisdom.co.in
- 13. 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 copy right @ www.pharmawisdom.co.in
- 16. 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 Folate Reductase Inhibitors: copy right @ www.pharmawisdom.co.in
- 18. Different Activities of Sulfonamide copy right @ www.pharmawisdom.co.in
- 19. 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. copy right @ www.pharmawisdom.co.in
- 20. 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, Adverse Effects copy right @ www.pharmawisdom.co.in
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- 22. A sulfone is a chemical compound containing a sulfonyl functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of two carbon atoms, usually in two separate hydrocarbon substituents. Dapsone Dapsone (diamino diphenyl sulfone, DDS), It was discovered by German chemists Fromm and Wittmann in 1908, Was not utilized as a treatment until decades later. Dapsone is used to treat dermatitis herpetiformis (a skin condition) and leprosy. It is also used with other drugs to treat Hansen's disease. Dapsone is commonly used in combination with rifampicin and clofazimine for the treatment of leprosy copy right @ www.pharmawisdom.co.in
- 23. Synthesis of Dapsone (Method-I)
- 24. Synthesis of Dapsone (Method-II)
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- 26. Drugs are great ! But they will ruin your life ! copy right @ www.pharmawisdom.co.in