Penicillins

It include introduction and history of penicillin, mechanism of action of penicillin, classification of penicillin, structural activity relationship of penicillin, adverse effects of penicillin and therapeutic uses of penicillin.

this presentation cover medicinal chemistry of penicillin.

1. PENICILLINS PREPARED BY KEVAL Y. RAVAL 7 TH SEM B.PHARM SHREE H.N. SHUKLA INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH

2. Contents Introduction and History Mechanism of action Classification SAR Adverse effects Therapeutic uses

3. Penicillin: Introduction and History Penicillin was derived from penicillium fungi. Penicillin was accidently discovered in 1928 by scientist Alexander Flemming . Penicillin is group of antibiotics that are used to treat infections which were deadly earlier. In their structure, beta-lactam ring is located due to this reason these are also called beta-lactam anti-biotics

4. Mechanism of action Penicillins are bactericidal as they kill micro-organisms when given in appropriate dose Synthesis of bacterial cell wall is depended upon an enzyme called transpeptidase Penicillin binds to penicillin-binding protein (PBP) and block transpeptidase enzyme. Which cause blockage in synthesis of bacterial cell wall and because of that reason bacteria die from cell lysis

5. Classification Penicillinase susceptible penicillins Penicillinase resistant penicillins Aminopenicillin Carboxypenicillin Uredopenicillin Miscellaneous penicillins

6. Classification: 1.Penicillinase susceptible penicillins

7. Classification: 2. Penicillinase resistant penicillins

8. Classification: 3 . Aminopenicillin

9. Classification: 4.Carboxypenicillin

10. Classification: 5.Ureidopenicillin

11. Classification: 6.Miscellaneous Penicillins

12. Extract of classification

13. Structural Activity Relationship Substitution on Thiazolidine ring Substitution on β- lactam ring

14. SAR 1.Substitution on Thiazolidine ring Substitution on position-1: sulfur When the sulfur atom of the thiazolidine ring is oxidized to a sulfone(SO2) or sulfoxide(SO), it improves acid stability but decreases the activity of the agent. Substitution on position-2: No substitutions are allow at this position, any chance will lower the activity Methyl groups are necessary Substitution on position-3: The carboxylic acid of ring is required for the activity If it’s changed to alcohol or ester, activity will decrease

15. SAR 1.Substitution on Thiazolidine ring Substitution on position 4: Nitrogen is required without any substitution for activity Substitution on position 5: Position 5 must be unsubstituted because Hydrogen of carbon-5 is required to maintain chirality and cis-formation of the compound for activity

16. SAR 2. Substitution on β- lactam ring (position-6) Substitution on position 6: Substitutions on position 6 can be explained using Penicillin-G (benzyl penicillin) as an example

17. SAR 2. Substitution on β- lactam ring (position-6) Stability of benzyl penicillin can further be increased by substitution using an electron withdrawing group (NH2,Cl,F,Br) at alpha position of benzyl penicillin Example, alpha-Substituted Benzyl penicillin are more stable then benzyl penicillin towards acid catalyzed hydrolysis

18. SAR 2. Substitution on β- lactam ring (position-6) Increasing steric hindrance at the alpha-carbon increases protection against β -lactamase resistance thus increases the activity. Steric hindrance: its slowing of the reaction because of the presence of bulky groups. β -lactamase resistance: Beta-lactamases are enzymes produced by bacteria that provide multi-resistance to β-lactam antibiotics such as penicillin.

19. SAR 2. Substitution on β- lactam ring (position-6) Substitution on ortho or meta position of benzyl ring also increase steric hindrance and protect drug from β -lactamase resistance and give more active compound. Examples: Methacillin (ortho substitution) Nefcillin (meta substitution) Bulkier substituents having 5-membered ring heterocylclic derivatives are required to have effective β -lactamase resistance. Examples: oxacillin, cloxacillin, dicloxacillin, fluoxacillin .

20. Adverse effects of penicillins Hypersensitivity reactions Super infections Diarrhea and GI disturbance convulsions

21. Therapeutic uses of Penicillin Streptococcal infections like pharyngitis, otitis media. Pneumococcal infections like pneumonia, pericarditis and meningitis. Syphilis and gonorrhea Meningococcal infections Actinomycosis Diphtheria tetanus

22. Reference James T. Park and Jack L. Strominger , Mode of Action of Penicillin, Science, New Series, Vol. 125, No. 3238 (Jan. 18, 1957), pp. 99-101. Neu , H. C. (1986). β-Lactam Antibiotics: Structural Relationships Affecting in Vitro Activity and Pharmacologic Properties. Clinical Infectious Diseases, 8(Supplement_3), S237–S259. Alexander flemming , on the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of b. influenza, May 10th, 1929. 2019, Chemdraw ultra 12.0, Chemdraw , PerkinElmer.