Chem167_L17_May30

Includes penicillin 1 derivakves cephalosporins 2

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Unformatted text preview: ate - para- aminobenzoic acid • Bind to the acKve site and block access to PABA • Reversible inhibiKon • Resistant strains produce more PABA Sulfonamide Mechanism of acKon Binding interacKons 2N H" " " H-Bond" van der Waals" interactions" Ionic bond" O" C" O" Active site" Normal substrate PABA H2" " "N O" S" O" NR" " Active site" sulfonamide Metabolic differences between bacterial and mammalian cells Dihydropteroate synthetase is present only in bacterial cells (selecKvity) Transport protein for folic acid is only present in mammalian cells (selecKvity) Can require resistance by producing more PABA (compeKKve inhibitor) Sulfonamides - Drug Metabolism O O H2N S O N HN S N-Acetylation HN Me S C O HN S O Sulfathiazole Notes • Sulfonamides are metabolised by N- acetylaKon • N- AcetylaKon increases hydrophobic character • Reduces aqueous solubility • May lead to toxic side effects N Insoluble metabolite Sulfonamides with reduced toxicity O O H2N S O H2N N S O N HN HN S N Sulfathiazole Sulfadiazine Notes • Thiazole ring is replaced with a pyrimidine ring • Pyrimidine ring is more electron- withdrawing • Sulfonamide NH proton is more acidic and ionisable • Sulfadiazine and its metabolite are more water soluble • Reduced toxicity • Silver sulfadiazine is used topically to prevent infecKon of burns H2N S O pKa 6.48 O O N HN N H2N S O N N N 86% Ionized Examples of Sulfonamides Sulfadoxine O H2N S O N HN N MeO OMe • Belongs to a new generaKon of sulfonamides • Long lasKng anKbacterial agent • Once weekly dosing regime • Sulfadoxine + pyrimethamine = Fani...
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