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Antibiotics: Penicillin
- 1. BETA LACTAM ANTIBIOTICS • Mr. Hitesh Vishwanath Shahare • Assistant Professor • Dept. Ph.’ Chem. •
- 2. Learners will be able to know; 2 1. Introduction and MOA 2. Classification & Development 3. SAR of Penicillin 4. Therapeutic uses & Adverse effect 4 3 2 1
- 3. Introduction 3 Contain beta lactam ring: It is a cyclic amide Beta lactam ring fused with other ring: Gives various beta lactam antibiotics……….. β-lactam ring portion of this group of antibiotics binds to different PBPs and unable them to perform their role in cell wall synthesis in Bacteria. Beta lactam + Thiazolidine Penicillin Beta lactam + Dihydrothiazine Beta lactam + Oxazolidinedione Cephalosporin Clavulanic acid Beta lactam + Pyrolline Thienamycin
- 4. 4 Beta lactam Antibiotics Penicillin Cephalosporin Carbepenem Monobactam Beta lactamase Inhibitors Clavulanic acid Sulbactam Tazobactam
- 5. 5 MOA Transpeptidase Beta Lactam ABs Bacterial cell wall : Composed of Peptidoglycan Consist of two amino sugars N-Acetylmuramic acid (NAM) N-Acetylglucosamine (NAG) Long strands & strength to bacterial cell wall Crosslinking Inhibit to Transpeptidase: No Crosslinking of AA Bacterial Cell Death NAM NAG Amino acid chain Peptidoglycan layer
- 6. 6 Penicillin
- 7. • Contain beta lactam ring: It is a cyclic amide 7 • Beta lactam ring fused with Thiazolidine: • Isolated from Penicillium chrysogenum / P. notatum in 1928 by Alexander Fleming (5R)-4-thia-1-azabicyclo[3.2.0]heptan-7-one Penam Penicillin
- 8. 8 Bacterial Culture Stap aureus Zone of Inhibition Penicillium Mould Alexander Fleming Florey & Chain 1940: Clinical Trial Microorganism produces a substance that kill other microorganism: Antibiosis
- 9. 9 During the second World war: Penicillin saved many lives as they used for infected wounds. Also Penicillin used to treat Diphtheria Gangrene Pneumonia Syphilis TB
- 10. 10 II Semi synthetic I Natural III Amino Penicillin IV Carboxy Penicillin Why Semisynthetic? -Penicillin has… Lack of Oral bioavailability, Succeptible to Hydrolysis, Penicillin G Enhanced Oral bioavailability, Resistant to enzyme Hydrolysis, Nafcillin Introduction of Amino group in side chain : Enhanced Oral bioavailability, Greater efficacy, Resistant to Hydrolysis, Amoxicillin Introduction of Carboxy group in side chain : Enhanced Oral bioavailability, Greater efficacy, Resistant to Hydrolysis, Carbenicillin Development of Penicillin
- 11. 11 • General structure • Carbon bearing amino group (C6) has l-configuration • Carbon bearing carboxyl group has d-configuration • Acyl amino group and carboxyl group are trans to each other 7 1 4 2 3 5 6 (2S,5R,6R)-6-Amino-3,3-dimethyl-7- oxo-4-thia-1-azabicyclo[3.2.0]heptane- 2-carboxylic acid • 3 chiral carbons: C3, C5 and C6 • All natural Penicillins are dextrorotatory
- 12. 12 CAS USP
- 13. 13 Acid Labile Penicillin Natural Semisynthetic Acid Resistant Penicillin G Penicillin V Penicillinase Resistant Beta lactamase inhibitors Extended Spectrum Methicillin, Cloxacillin, Flucloxacillin Clavulanic acid, Sulbactam, Tazobactam Aminopenicillin: Ampicillin Carboxypenicillin: Carbenicillin Uriedopenicillin: Piperacillin
- 14. 14 Penicillin Penicilloic acid Penilloic acidPenicillamine Penillo aldehyde Penicillanase Or NaOH Heat -CO2 Strong Acid HgCl2/ Water • Side Chain split by Amidase • Beta Lactam ring Broken by beta- lactamase
- 15. 15 Thiazolidine ring Beta lactam Acyl Amino Side Chain 1 2 3 1) Sulfur atom at position 1 when oxidized to sulfone or sulfoxide: More acid stable but with reduced activity. 2) Substitution at position 2: Dimethyl groups are essential for activity-any change reduce the activity. 3) Substitution at position 3: Carboxylic acid essential for activity and require for –PBP recognition. Carboxylate ion binds to charged nitrogen of lysine residues in binding site If change to ester- becomes Prodrug and bioavailability increases.
- 16. 16 4) Position 5 should be unsubstituted. 5) Position 6 can be substituted with variable groups on amide side chain. Substitution (R) with Electron withdrawing groups in amide side chain: Increases stability towards the acid-because amide oxygen becomes less Nucleophillic Substitution (R) with Bulky groups in amide side chain: Make more resistant to beta lactamase enzyme: Steric hindrance protect from beta lactamase enzyme 6) Position 7 Carbonyl group: Form resonance stabilized structure for Nucleophillic attack 7) Position C5 & C6: Cis Stereochemistry: Essential for activity 6 5 7 Substitution (R) with polar/ionized/acidic groups in amide side chain: Make more active against Gram -ve bacteria
- 17. 17
- 18. Drugs and Preparations 18 (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4- thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Benzyl Penicillin (Penicillin G) 3,3-Dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid Phenoxymethyl Penicillin (Penicillin V)
- 20. 5 September 2020 SNJB's SSDJ College of Pharmacy, Chandwad (Nasik) 20 (2S,5R,6R)-6-{[carboxy(phenyl)acetyl]amino}- 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid (2S,5R,6R)-6-{[(2R)-2-carboxy-2-(3- thienyl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid Carbenicillin Ticarcillin Carboxypenicillins
- 22. Penicillinase Resistant Drugs 22 Oxacillin Cloxacillin Dicloxacillin Flucloxacillin
- 23. 23 Free Penicillin is not suitable for oral and parenteral administration: So, utilized in their Sodium or Potassium salt form.
- 24. 24 Hypersensitivity Pain at site of Injection
- 25. 5 September 2020 SNJB's SSDJ College of Pharmacy, Chandwad (Nasik) 25 Thank You! hvshahare@gmail.com