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Penicillins by Dr. Panchumarthy Ravisankar M.Pharm., Ph.D.

Dr. Panchumarthy Ravisankar M. Pharm., Ph.D.
Introduction
Historical background
Classification
Biological sources & Nomenclature
Basic structure & SAR
Structures of different Penicillins
Chemical degradation & Biosynthesis
Mechanism of action
Therapeutic uses & Toxicity
Advantages & Disadvantages

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Penicillins by Dr. Panchumarthy Ravisankar M.Pharm., Ph.D.

  1. 1. 1 Introduction Historical background Classification Biological sources & Nomenclature  Basic structure & SAR Structures of different Penicillins Chemical degradation & Biosynthesis Mechanism of action Therapeutic uses & Toxicity Advantages & Disadvantages By Dr. Panchumarthy Ravisankar M.Pharm, Ph.D. K. Manjusha Vignan Pharmacy College Vadlamudi -522 213. Guntur Dist Andhra Pradesh INDIA.
  2. 2. CONTENTS:  Introduction  Historical background  Classification  Biological sources & Nomenclature  Basic structure & SAR  Structures of different Penicillins  Chemical degradation & Biosynthesis  Mechanism of action  Therapeutic uses & Toxicity  Advantages & Disadvantages Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 2
  3. 3. INTRODUCTION:  The term antibiotic came from the word antibiosis coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life.  Defined as chemical substances produced by various species of microbes such as bacteria & fungi, in low concentrations destroy or inhibit the growth of other species of microbes. Anti = against Bios = life Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 3
  4. 4.  Antibiotics are classified based on structure, spectrum, source & pharmacological activity.  Based on the structure antibiotics are of different types like β lactams, Aminoglycosides, Tetracyclines, Macrolides, polypeptides, Quinolines, Sulfa antibiotics & miscellaneous.  PENICILLINS comes under β-LACTAM CLASS OF ANTIBIOTICS. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 4
  5. 5. Antibioticsareclassifiedbased onstructure,spectrum,source& pharmacologicalactivity. Basedonthestructure antibioticsareofdifferenttypes like βlactams,Aminoglycosides, Tetracyclines,Macrolides, polypeptides,Quinolines,Sulfa antibiotics&miscellaneous. PENICILLINScomesunderβ- LACTAM CLASSOFANTIBIOTICS. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 5
  6. 6. • Antibiotics are classified based on structure, spectrum, source & pharmacological activity. • Based on the structure antibiotics are of different types like • β lactams, Aminoglycosides, Tetracyclines, Macrolides, polypeptides, Quinolines, Sulfa antibiotics & miscellaneous. • PENICILLINS comes under β-lactam class of antibiotics. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 6
  7. 7. HISTORICAL BACKGROUND OF PENICILLINS  In 1928 ALEXANDER FLEMMING discovered penicillin from the fungus Penicillium notatum.  Observed that colonies of S. aureus failed to grow in the areas contaminated by Penicillium notatum.  He isolated the mould, grew it in a fluid medium and found that it produced a substance capable of killing many of the common bacteria that infect humans.  He coined the term PENICILLIN. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 7
  8. 8.  It was unstable and he was unable to purify.  FLOREY & CHAIN used Freeze drying & Chromatography to isolate penicillin & shared the Noble prize with Fleming.  In June 1948 penicillin was available to treat 10 patients.  After fermentation research 2.3 million doses had been increased in U.S. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 8
  9. 9. CLASSIFICATION OF PENICILLINS source Route of administration Based on spectrum of activity Resistant to hydrolyzing enzyme Resistant to acids 1.Natural 1.Oral 1.Narrow spectrum 1.Resistant to 1.Acid Penicillin G Amoxycillin Methicillin beta lactamase stable Peniciilin V Oxacillin Oxacillin Methicillin PenicillinG 2.Biosynthetic Cloxacillin Dicloxacillin Oxacillin Oxacillin Penicillin G Dicloxacillin Nafcillin Cloxacillin Cloxacillin Penicillin V Ampicillin 2.Broad spectrum Dicloxacillin Ampicillin Penicillin X Ampicillin 2.Non resistant 2.Acid Penicillin F 2.Parenteral Amoxycillin to beta lactamase unstable Penicillin K Penicillin G 3.Intermediate spectrum Penicillin G Ticarcillin 3.Semisynthetic Methicillin Penicillin G Penicillin V Methicillin Oxacillin Nafcillin Penicillin v Ampicillin Piperacillin Cloxacillin Carbencillin 4.Extended spectrum Amoxycillin Dicloxacillin Ticarcillin Carbencillin Carbencillin Ampicillin Ticarcillin Methicillin Azocillin Mezlocillin 9
  10. 10. BIOLOGICAL SOURCES OF PENICILLINS:  Benzyl penicillin obtained by fermentation from Penicillium notatum.  Now it is from a high yielding strain Penicillium chrysogenum. NOMENCLATURE 1. Chemical Abstract System (CAS): Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 10 6-acylamino-2,2-dimethyl-3- carboxylic acid. CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin 4 3 2 1 56 7
  11. 11. 2.United states pharmacopoeia: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 11 4-Thia-1-aza-bicyclo[3.2.0] heptane • Reverse of CAS system. 3.As derivatives of Penam: PENAM - Unsubstituted bicyclic system with carbonyl group. N S O 1 2 56 7 4 3 4-thia-1-azabicyclo[3.2.0]heptan-7-one CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin 4 3 21 56 7
  12. 12. 4.As derivatives of Penicillanic acid:  Penicillins are named as derivatives of Penicillanic acid ring system with 2,2-dimethyl and carboxyl group as substituents at 2nd and 3rd positions. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 12 N S CH3 CH3 COOH H2N HH O H 1 2 3 4 5 7 6 6-Amino penicillanic acid
  13. 13. 5.As derivatives of penicillin:(on the basis of “R” group) … TRIVAL SYSTEM  6-carbonyl amino penicillanic acid portion of the molecule is named as penicillin.  This system is simple and serves as a good measure for naming and comparing closely related penicillin structures.  Not well suited for compounds having the ring modified derivatives. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 13
  14. 14. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 14
  15. 15. Basic structure of Penicillin: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 15 Acyl amino side chain 6-Amino penicillanic acid H C C N H C C C S O CH3 CH3 COO- H HNCR O Free carboxylate Cis stereochemistry Most reactive carbonyl group Site of Penicillinase action Basic chemistry:Beta lactum ring+Thiazolidine ring Bicyclic ring system sysyem is essential Variable group Beta lactum ring Thiazolidine ring Methyl groups
  16. 16.  Shape of the molecule is like a Half open book.  Has 3 chiral centers at C-3 , C-5 ,C-6.  Disruption of these lead to loss of activity.  Acyl amino side chain is essential for biological activity.  Variable group R determines the stability and improved spectrum of activity. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 16
  17. 17. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 17 STRUCTURALACTIVITY RELATIONSHIP : 1 2 3 4 56 7
  18. 18. Structures of different Penicillins: Penicillin G:  Acid unstable.  Parenteral route.  Self destructive mechanism in its structure because of influence of acyl side chain.  Has gram positive potency against susceptible Staphylococci, Streptococci. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 18 N S CH3 CH3 COOH O HNCH2C O H H H
  19. 19. Penicillin V:  More acid stable then Penicillin G.  Administered by oral route.  Has electronegative oxygen on the acyl side chain with electron withdrawing effect which has the ability to solve acid sensitivity. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 19 N S CH3 CH3 COOH O HNCH2C O O H H H
  20. 20. Methicillin:  Has no electron withdrawing group on the side chain.  Acid sensitive and has to be injected.  Steric shields can be added to penicillins to protect from penicillinase enzyme.  Bulky groups on the side chain prevent the penicillinase enzyme to reach the penicillinase active site. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 20 N S CH3 CH3 COOH O HNC O H H H CH3 CH3
  21. 21. O N SNH COOH CH3 CH3 C O Isoxazolyl Penicillins O N CH3 R1 R2 R1 R2 Oxacillin H H Cloxacillin Cl H Dicloxacillin Cl Cl Better penicillinase resistant agents have been developed. The isoxazolyl ring acts as the steric shield but It is also electron-withdrawing giving the Structure acid stability. Flucloxacillin Cl F Bulky and electron withdrawing
  22. 22. Isoxazolyl penicillins:  Penicillinase resistant penicillins.  Ring acts as steric shield and also a electron withdrawing group giving acid stability to the structure. R1 R2 Oxacillin H H Cloxacillin Cl H Dicloxacillin Cl Cl Flucloxacillin Cl F Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 22 N S CH3 CH3 COOH O HNC H H N O R1 R2 CH3 O H
  23. 23. Ampicillin:  If hydrophilic groups like (NH2, OH , COOH ) are attached to the carbon that is α to the carbonyl group on the side chain then α hydrophilic group aids the passage of penicillins through porins of gram –ve bacteria.  Susceptable to degradation of penicillins.  Hence given in combination with β lactamase inhibitors like Sulbactum ,Gentamycin. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 23 N S CH3 CH3 COOH O HNC H H HC O H NH2
  24. 24. Amoxycillin:  β hydroxy ampicillin.  Better absorbed through gut wall due to presence of hydroxyl goup.  Same spectrum of activity as that of penicillin G but more active against gram–ve bacteria.  Acid resistant hence given orally.  Non toxic. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 24 N S CH3 CH3 COOH O HNC H H HC O H NH2 HO
  25. 25. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 25 R R Nafcillin Ticarcillin Carbenicillin Piperacillin C2H5O H C COOH C2H5NN O O S HC COOH CH C N H C C C S O COOH CH3 CH3 HNCR O H
  26. 26. Chemical degradation: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 26 CH C HN H C C C S CH3 COOH HO O CH3 H HNCR O Penicilloic acid Penicillinase or NaOH CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin HN S COOH CH3 CH3 H H2CHNCR O Penilloic acid R C NH O H2 C CHO Penillo aldehyde HC C CH3 CH3 COOH HS H2N Penicillamine -CO2 Heat HgCl2 / Water+ Strong acid
  27. 27. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 27 CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin CH C HN H C C C S CH3 COOH H3CO O CH3 H HNCR O Methyl penicillate R C NH O C H CHO Methyl penaldate COCH3 HC C CH3 CH3 COOH HS H2N Penicillamine N N S CH3 COOH CH3 H HH HOOC R Penillic acid CH3OH HgCl2 / Water + dil.acid pH 2
  28. 28. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 28 CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin N O OHC R NH CH COOH C H3C H3C SH Penicillenic acid HC C CH3 CH3 COOH HS H2N Penicillamine R C NH O C C H COOH NH H C COOH C CH3 HS CH3 Penamaldic acid C O NHR H C CHO COOH Penaldic acid R C NH O H2 C CHO Penillo aldehyde pH 4 H2O + H + -CO2
  29. 29. Enzymatic hydrolysis with Penicillinase or β lactamase: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 29 CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin CH C HN H C C C S CH3 COOH HO O CH3 H HNCR O Penicilloic acid Penicillinase or Beta lactamase CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin N S COOH CH3 H2N CH3 H O H H 6-APA + RCOOH Amidase Penicillin acylase By product Enzymatic hydrolysis with Amidase:
  30. 30. Synthesis of Penicillins from 6-APA:  Production of 6-APA: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 30 CH C N H C C C S O COOH CH3 CH3 HNCR O H Penicillin N S COOH CH3 H2N CH3 H O H H 6-APA + RCOOH Penicillin acylase
  31. 31. • Synthesis of Penicillin G from 6-APA: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 31 N S COOH CH3 H2N CH3 H O H H 6-APA + CH2COCl 2-phenylacetyl chloride -HCl N S O HN CH3 COOH CH3 HH H CH2C O Penicillin G
  32. 32. Bacteristatic Antibiotics Bactericidal Penicillins Inhibit the synthesis of peptidoglycon layer containing NAM &NAG connected by penicillin binding proteins(PBP) Acts on PBP and inhibits the synthesis of Peptidoglycon. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 32 Mechanism of action: Gram +ve Gram -ve Cell membrane Peptidoglycon cell wall Lipopolysacc haride layer
  33. 33. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 33
  34. 34. (Peptidoglycan cell wall) N-acetylglucosamine N-acetylmuramic acid Transpeptidases located within the cell membrane are responsible for cross linking the Peptidoglycan chains Transpeptidases (Penicillin Binding Proteins) In order to make the rigid grid, There is an enzyme called Transpeptidase,which connects the Little peptide strings perpendicular to the NAM and NAG chains. Cell membrane PBP’S (or) transpeptidase help to build Or construct maintain the peptidoglycon Layer.
  35. 35. (Cell membrane) (Peptidoglycan cell wall) Penicillin’s inactivate the transpeptidase enzyme by covalently bonding to the serine residues within the active site. Bonding is by acetylation Transpeptidases (Penicillin Binding Proteins) S O PBP’S are present in bacterial cell membrane Which are involved in the synthesis of cell wall Betalactum antibiotics (or)
  36. 36. Beta lactamase Inhibitors:  Has negligible antibacterial activity.  Given with Penicillins which increases spectrum of activity.  Microbial resistance to beta lactam antibiotics. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 36 N S O HN S O OH Beta alctamase
  37. 37. β lactam antibiotics β lactam enzyme + β lactamase inhibitor Contain β lactum ring Complex Catalysing the β lactamases hydrolysis of β lactum ring Effectiveness of β lactamase is diminished INACTIVE COMPOUNDS Enhances the activity of β lactam antibiotics Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 37
  38. 38. Clavulanic acid:  Isolated from Streptomyces clavuligerus.  1st naturally occuring β lactum ring that was not fused to a ‘S’ containing ring. Sulbactum:  β lactamase disabiling agent.  Prepared by partial chemical synthesis from penicillins. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 38 N O O H COOH H H OH N S O COO-Na+ H O CH3 CH3 O H
  39. 39. Tazobactum:  Co-administered with Piperacillin.  Has little or no antibacterial activity. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 39 N S O COO- O CH3 O H N N N Beta lactamase Inhibitors: Available agents β-lactamase binding Potency Clavulanic acid + + + + + + Sulbactam + + + + + + Tazobactam + + + + + + + +
  40. 40. Combinations of penicillins with β lactamase inhibitors: Amoxicillin + Clavulanic acid = Clavulin Ticarcillin + Clavulanic acid = Timentin Piperacillin + Tazobactam = Tazocin Ampicillin + Sulbactum = Unasyn Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 40
  41. 41. Therapeutic uses:  Skin & soft tissue infections.  Diphtheria, tetanus, gas gangrene.  Intra abdominal infection, syphilis.  Ear, nose, lungs infections.  Streptococcal infections.  Drug of choice for Anthrax, Trench mouth, Rat bite fever, Actinomycosis. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 41
  42. 42.  Ampicillin & Amoxycillin HELPS to clear Enterococci infections. H- Heamophilus Influenzae E- Escherichia coli L- Listeria monocytogene P- Proteus mirabilis S- Salmonella typhi Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 42
  43. 43. Toxicity of Penicilins:  Some people experience side effects.  Serious allergic reaction is Anaphylaxis which is fatal.  Broad spectrum antibiotics like Ampicillin by oral route alters flora in intestine and leads to GIT disturbances.  High dosages of parenteral penicillins in renal patients has induced CNS effects.  Nausea, dizziness, bronchospasm, sore mouth & tongue, skin rashes, angio odema. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 43
  44. 44. Hypersensitivity or Allergic reactions:  Caused by degradation products of penicillin.  3 types of hypersensitivity. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 44 Immediate Accelerated Late Occurs within 20mins Within 72 hrs After 72 hrs Prurities,skin rashes, Wheezing, sneezing, rhinitis Skin rashes, fever, angioneurotic oedema, utricaria +ve heamolytic anemia, utricaria, skin rashes, local inflammation, serum sickness
  45. 45. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 45
  46. 46. Advantages:  Have excellent tissue penetration.  Bactericidal against sensitive strains.  Relatively nontoxic.  Efficacious in the treatment of infections.  Inexpensive in comparision with other antibiotics.  Newer penicillin's are resistant to stomach acid, such as penicillin V, or have a broader spectrum, such as ampicillin and amoxicillin. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 46
  47. 47. Disadvantages:  Acid liability - most of these drugs are destroyed by gastric acid  Lack of activity against most Gram-negative organisms.  Short duration of action - because of this short half-life, the penicillin's must be administered at short intervals, usually every 4 hours.  Drug hypersensitivity - about 10% of population has allergy.  Many patients experience GI upset.  Painful if given intramuscularly. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 47
  48. 48. Keypoints:  Penicillins have a bicyclic structure consisting of a β-lactam ring fused to a thiazolidine ring.  Strained β -lactam ring reacts irreversibly with the transpeptidase enzyme responsible for the final cross-linking of the bacterial cell wall.  Penicillin analogues can be prepared by fermentation or by a semi- synthetic synthesis from 6-APA. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 48
  49. 49.  Variation of the penicillin structure is limited to the acyl side chain. Penicillins can be made more resistant to acid conditions by incorporating an electron-withdrawing group into the acyl side chain.  Steric shields can be added to penicillins to protect them from bacterial β-lactamase enzymes.  Broad-spectrum activity is associated with the presence of an α- hydrophilic group on the acyl side chain of penicillin. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 49
  50. 50. CONCLUSION  Penicillin antibiotics were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci & are still widely used today though many types of bacteria have developed resistance .  About 10% of people report that they are allergic to penicillin; however, 90% of this group are not actually allergic.  There are several enhanced penicillin families which are effective against additional bacteria; these include the antistaphylococcal penicillins, aminopenicillins &antipseudomonal penicillins. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 50
  51. 51. References:  William O. Foye, Textbook of Medicinal Chemistry, Lea & Febiger, Philadelphia. Pg no: 1046 – 1059  JH Block & JM Beale, Wilson & Giswold’s Textbook of Organic Medicinal Chemistry & pharmaceutical chemistry by (Eds), 11th Ed, Lipincott, Raven, Philadelphia,2004  Sriram, Medicinal Chemistry. Pg no: 294-395  Kadam, Textbook of Medicinal Chemistry. Pg no: 120-131  Ilango, Principles of Medicinal chemistry(vol.1). Pg no: 5.2-5.10  G.L.Patrick, Introduction to Medicinal Chemistry. Pg no:429-453 Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 51
  52. 52. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P) 52

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