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Introduction • WHO; Tuberculosis in 2002, 2,000,000 death, 1/3 of the world’s population was infected. • 1,900,000 children died worldwide of respiratory infections with 70% of these deaths in Africa and Asia. © Oxford University Press, 2013 History of antibacterial agents • • • • Old age Mouldy soybean curd in Chinese Wine, myrrh, inorganic salts in Greek Certain type of honey in Middle age. Identification of bacteria : van Leeuwenhoek in 1670s Fermentation by microorganism: Pasteur Germ theory of disease : Lister The reason of tuberculosis is microorganism, vaccination: Koch The principle of chemotherapy; Ehrlich’s Magic bullet, selective toxicity, chemotherapeutic index, therapeutic index. © Oxford University Press, 2013 © Oxford University Press, 2013 Classification of bacteria : Appendix 5 Difference of bacterial and animal cells - defined nucleus -Organelles -Biochemistry, e.g. vitamin synthesis -Cell wall, osmotic pressure, lysis © Oxford University Press, 2013 Five main mechanisms of antibacterial action 1.Inhibition of cell metabolism: sulphonamide 2.Inhibition of bacterial cell wall synthesis : penicillin, cephalosporins, cycloserine, vancomycin 3.Interactions with the plasma membrane: polymyxins, tyrothricin 4.Disruption of protein synthsis: rifamycins, streptomycin, tetracyclines, chloramphenicol 5. Inhibitions of nucleic acid transcription and replication: nalidixic acid, proflavin, quinolones, aminoacridines © Oxford University Press, 2013 SULPHONAMIDES O R1HN S O NHR2 © Oxford University Press, 2013 1. Lead Compound O O N H2N S N NH2 O NH2 Pront osi l Metabol i sm H2N S O NH2 Sul fani l ami de 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 © Oxford University Press, 2013 2. Structure-Activity Relationships para-Amino group R1HN Aromatic O S Sulphonamide 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 © Oxford University Press, 2013 3. Prodrugs of sulfonamides O HN S 2 Me O - CH3CO2H O NHR Enzyme H2N S O 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 © Oxford University Press, 2013 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 © Oxford University Press, 2013 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 © Oxford University Press, 2013 6. Mechanism of action H2N N H2N N H2N CO2H OP P N H O N H N HN para-Aminobenzoic acid HN N N H Dihydropteroate synthetase _ Reversible O CO2H inhibition Dihydropteroate Sulphonamides H2N H2N H CO2H N N H N HN N H CO2H H N O L-Glutamic acid CO2H Dihydrofolate O H2N N H Dihydrofolate reductase NADPH H N CO2H Trimethoprim _ H N HN N H O Tetrahydrofolate (coenzyme F) H N O H CO2H CO2H © Oxford University Press, 2013 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 © Oxford University Press, 2013 6. Mechanism of action Binding interactions O H2 N O C H2 N O S NR O Active site Active site H-Bond van der Waals interactions Ionic bond © Oxford University Press, 2013 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 © Oxford University Press, 2013 7. Sulphonamides - Drug Metabolism O H2N S O O N N-Acetylation HN S Sulphathiazole Me HN S C HN O N S O Insoluble metabolite Notes •Sulphonamides are metabolised by N-acetylation •N-Acetylation increases hydrophobic character •Reduces aqueous solubility •May lead to toxic side effects © Oxford University Press, 2013 8. Sulfonamides with reduced toxicity O O H2N S O H2 N N 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 H2 N S O pKa 6.48 O O N HN N H2N S O N N N 86% I oni zed © Oxford University Press, 2013 9. Examples of Sulphonamides Sulphadoxine O H2 N 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 Cl Pyrimethamine NH2 © Oxford University Press, 2013 9. Examples of Sulphonamides Succinyl sulphathiazole O O HN S HO2C O N HN O2C O Succinyl sulphathiazole S H2N Enzyme S O N HN CO2H S 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 © Oxford University Press, 2013 9. Examples of Sulphonamides Benzoyl prodrugs O HN S NHR2 C H2N C S Benzoic acid O NHR2 O O Benzoyl prodrug O OH O Sulphonamide •Too hydrophobic to cross gut wall •Slowly hydrolysed by enzymes in gut •Used versus gut infections © Oxford University Press, 2013 9. Examples of Sulphonamides NH2 N O H2N H2N N OMe S O Me HN N MeO Trimethoprim O OMe 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 © Oxford University Press, 2013 10. Sulphones NH2 N H2N O S O N NHR1 •Thought to inhibit dihydropteroate synthetase •Used in the treatment of leprosy © Oxford University Press, 2013