Sulfonamides _ Sulphones.ppt

SULPHONAMIDES O 1 R HN S O NHR2 Kwabena F.M. Opuni This presentatio...

SULPHONAMIDES O 1 R HN S O NHR2 Kwabena F.M. Opuni This presentation is adapted from Oxford University Press slides from “An Introduction to Medicinal Chemistry 5th Edition by Graham L. Patrick” 1. Lead Compound O O N S O Metabolism H2N S O H2N N NH2 NH2 Prontosil Sulfanilamide NH2 Notes Prontosil - red dye Antibacterial activity in vivo (1935) Inactive in vitro Metabolised to active sulphonamide Acts as a prodrug Sulphanilamide - first synthetic antibacterial agent acting on a wide range of infections 2. Structure-Activity Relationships para-Amino Aromatic para-Amino O Sulphonamide group R1HN S O NHR2 Primary amino group is essential (R1=H) Amide groups (R1=acyl) are allowed inactive in vitro, but active in vivo act as prodrugs Aromatic ring is essential para-Substitution is essential Sulphonamide group is essential Sulphonamide nitrogen must be primary or secondary R2 can be varied 3. Prodrugs of sulfonamides O - CH3CO2H O HN S O H2N S O Me NHR2 Enzyme NHR2 O Notes Amide group lowers the polarity of the sulphonamide 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 ionises and can form ionic interactions Ionised primary amine also acts as a strong HBD 4. Sulphanilamide analogues O R1HN S O NHR2 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 5. Sulphanilamides - applications Notes Antibacterial drugs of choice prior to penicillins (1930s) Superseded by penicillins Current uses Treatment of urinary tract infections Eye lotions Treatment of gut infections Treatment of mucous membrane infections 6. Mechanism of action H2N N N H2N CO2H H2N N N H para-Aminobenzoic acid HN N N HN OP P H N Dihydropteroate synthetase H O _ Reversible CO2H O inhibition Dihydropteroate Sulphonamides H2N N N H2N CO2H H HN N H CO2H N H H L-Glutamic acid O N CO2H Dihydrofolate H CO2H O Dihydrofolate reductase Trimethoprim H _ H2N N N NADPH H HN N N H H O N CO2H Tetrahydrofolate (coenzyme F) H CO2H O 6. 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 Sulphonamides 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 6. Mechanism of action Binding interactions O O H2 N C H2 N S NR O O Active site Active site H-Bond van der Waals interactions Ionic bond 6. Mechanism of action Metabolic differences between bacterial and mammalian cells Dihydropteroate synthetase is present only in bacterial cells Transport protein for folic acid is only present in mammalian cells 7. Sulphonamides - Drug Metabolism O O H2N S O N HN S O N HN N-Acetylation Me C HN S O S Sulphathiazole Insoluble metabolite Notes Sulphonamides are metabolised by N-acetylation N-Acetylation increases hydrophobic character Reduces aqueous solubility May lead to toxic side effects 8. Sulfonamides with reduced toxicity O O H2N S O N H2N S O N HN HN S N Sulphathiazole Sulphadiazine Notes Thiazole ring is replaced with a pyrimidine ring Pyrimidine ring is more electron withdrawing Sulphonamide NH proton is more acidic and ionisable Sulphadiazine and its metabolite are more water soluble Reduced toxicity Silver sulphadiazine is used topically to prevent infection of burns O O pKa 6.48 H2N S O N H2N S O N N HN N N 86% Ionized 9. Examples of Sulphonamides Sulphadoxine O H2N S O N HN N MeO OMe Belongs to a new generation of sulphonamides Long lasting antibacterial agent Once weekly dosing regime Sulphadoxine + pyrimethamine = Fanisdar Used for the treatment of malaria N NH2 H3C N Pyrimethamine NH2 Cl 9. Examples of Sulphonamides Succinyl sulphathiazole O O HO2C HN S O H2N S O N N Enzyme HN HN CO2H S O2C O S Succinyl sulphathiazole Succinic acid Sulphathiazole Notes Acts as a prodrug of sulphathiazole Ionised in the slightly acidic conditions of the intestine Too polar to cross the gut wall Concentrated in the gut Slowly hydrolysed by enzymes in the gut Used versus gut infections 9. Examples of Sulphonamides Benzoyl prodrugs O OH O HN S O C H2N S O C NHR2 O NHR2 O Benzoyl prodrug Benzoic acid Sulphonamide Too hydrophobic to cross gut wall Slowly hydrolysed by enzymes in gut Used versus gut infections 9. Examples of Sulphonamides NH2 N H2N O O Me N H2N S OMe HN O N MeO OMe Trimethoprim Sulphamethoxazole Sulphamethoxazole + trimethoprim = co-trimoxazole Agents inhibit different enzymes in same biosynthetic pathway Strategy of sequential blocking Allows lower, safer dose levels of each agent 10. Sulphones NH2 N O H2N S O N NHR1 Thought to inhibit dihydropteroate synthetase Used in the treatment of leprosy