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SULFONAMIDES

SULFONAMIDES. Chapter 19. Lead Compound. Notes Prontosil - red dye Antibacterial activity in vivo (1935) Inactive in vitro Metabolised to active sulfonamide Acts as a prodrug Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections.

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SULFONAMIDES

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  1. SULFONAMIDES Chapter 19

  2. Lead Compound • Notes • Prontosil - red dye • Antibacterial activity in vivo (1935) • Inactive in vitro • Metabolised to active sulfonamide • Acts as a prodrug • Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections

  3. Structure-Activity Relationships Aromatic para-Amino group Sulfonamide • para-Amino group is essential (R1=H) • para-Amido groups (R1=acyl) are allowed • inactive in vitro, but active in vivo • act as prodrugs • Aromatic ring is essential • para-Substitution is essential • Sulfonamide group is essential • Sulfonamide nitrogen must be primary or secondary • R2 can be varied

  4. Enzyme Prodrugs of sulfonamides • Notes • Amide group lowers the polarity of the sulfonamide • Amide cannot ionise • Alkyl group increases the hydrophobic character • Crosses the gut wall more easily • Metabolised by enzymes (e.g. peptidases) in vivo • Metabolism generates the primary amine • Primary amine ionizes and can form ionic interactions • Ionised primary amine also acts as a strong HBD

  5. Sulfanilamide analogues • Notes • R2 is variable • Different aromatic and heteroaromatic rings are allowed • Affects plasma protein binding • Determines blood levels and lifetime of the drug • Affects solubility • Affects pharmacokinetics rather than pharmacodynamices

  6. Sulfanilamides - applications • Notes • Antibacterial drugs of choice prior to penicillins (1930s) • Superseded by penicillins • Current uses • Treatment of urinary tract infections • Eye lotions • Treatment of gut infections • Treatment of mucous membrane infections

  7. para-Aminobenzoic acid Dihydropteroate synthetase Reversible inhibition Dihydropteroate Sulfonamides L-Glutamic acid Dihydrofolate Dihydrofolate reductase NADPH Trimethoprim _ _ Tetrahydrofolate (coenzyme F) Mechanism of action

  8. Mechanism of action • Target enzyme • Dihydropteroate synthetase - bacterial enzyme • Not present in human cells • Important in the biosynthesis of the tetrahydrofolate cofactor • Cofactor is crucial to pyrimidine and DNA biosynthesis • Crucial to cell growth and division • Sulfonamides • Competitive enzyme inhibitors • Bacteriostatic agents • Not ideal for patients with weakened immune systems • Mimic the enzyme substrate - para-aminobenzoic acid (PABA) • Bind to the active site and block access to PABA • Reversible inhibition • Resistant strains produce more PABA

  9. O O C S H H N N N R 2 2 O O van der Waals interactions Ionic bond Active site Active site H-Bond Mechanism of action Binding interactions

  10. Mechanism of action Metabolic differences between bacterial and mammalian cells Dihydropteroatesynthetase is present only in bacterial cells Transport protein for folic acid is only present in mammalian cells

  11. N-Acetylation Sulfathiazole Insoluble metabolite Sulfonamides - Drug Metabolism • Notes • Sulfonamides are metabolised by N-acetylation • N-Acetylation increases hydrophobic character • Reduces aqueous solubility • May lead to toxic side effects

  12. Sulfathiazole Sulfadiazine Sulfonamides with reduced toxicity • Notes • Thiazole ring is replaced with a pyrimidine ring • Pyrimidine ring is more electron-withdrawing • Sulfonamide NH proton is more acidic and ionizable • Sulfadiazine and its metabolite are more water soluble • Reduced toxicity • Silver sulfadiazine is used topically to prevent infection of burns

  13. Sulfadoxine • Belongs to a new generation of sulfonamides • Long lasting antibacterial agent • Once weekly dosing regime • Sulfadoxine + pyrimethamine = Fanisdar • Used for the treatment of malaria Pyrimethamine Examples of Sulfonamides

  14. Succinyl sulfathiazole Enzyme Succinyl sulfathiazole Succinic acid Sulfathiazole Examples of Sulfonamides • Notes • Acts as a prodrug of sulfathiazole • Ionized in the alkaline conditions of the intestine • Too polar to cross the gut wall • Concentrated in the gut • Slowly hydrolysed by enzymes in the gut • Used for gut infections

  15. Benzoyl prodrugs Benzoyl prodrug Benzoic acid Sulfonamide • Too hydrophobic to cross gut wall • Slowly hydrolyzed by enzymes in gut • Used for gut infections Examples of Sulfonamides

  16. Sulfamethoxazole + trimethoprim = co-trimoxazole • Agents inhibit different enzymes in same biosynthetic pathway • Strategy of sequential blocking • Allows lower, safer dose levels of each agent Trimethoprim Sulfamethoxazole Examples of Sulfonamides

  17. Thought to inhibit dihydropteroatesynthetase • Used in the treatment of leprosy Sulfones

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