Chem167_L17_May30

Sulfonamides drug metabolism o o h2n s o n hn s n

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Unformatted text preview: rugs Structure- AcKvity RelaKonships para- Amino group R1HN AromaKc Sulfonamide O S O NHR2 • para- Amino group is essenKal (R1=H) • para- Amido groups (R1=acyl) are allowed • inacKve in vitro, but acKve in vivo • act as prodrugs • AromaKc ring is essenKal • para- SubsKtuKon is essenKal • Sulfonamide group is essenKal • Sulfonamide nitrogen must be primary or secondary • R2 can be varied Prodrugs of sulfonamides O HN S NHR2 Me O - CH3CO2H O Enzyme O 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. pepKdases) in vivo • Metabolism generates the primary amine • Primary amine ionises and can form ionic interacKons • Ionised primary amine also acts as a strong HBD H2N S O NHR2 Sulfanilamides - applicaKons Notes • AnKbacterial drugs of choice prior to penicillins (1930s) • Superseded by penicillins Current uses • Treatment of urinary tract infecKons • Eye loKons • Treatment of gut infecKons • Treatment of mucous membrane infecKons Sulfonamide Mechanism of acKon H2N N HN H2N N H2N CO2H para-Aminobenzoic acid OP P N H N HN Dihydropteroate synthetase _ Reversible " Dihydropteroate inhibition Sulfonamides H2N H2N H CO2H CO2H N HN L-Glutamic acid N N H O H N H N Dihydrofolate O H2N N HN N H O O N O Tetrahydrofolate" (coenzyme F) H Dihydrofolate" reductase" NADPH H N N H CO2H CO2H _ Trimethoprim H N H N O H CO2H CO2H H N CO2H Sulfonamide Mechanism of acKon 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 • CompeKKve enzyme inhibitors • Bacteriosta5c agents • Not ideal for paKents with weakened immune systems • Mimic the enzyme substr...
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This note was uploaded on 01/15/2014 for the course CHEM 167 taught by Professor Amaro during the Winter '13 term at UCSD.

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