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

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.

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

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

 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.

Antibioticsareclassifiedbased
onstructure,spectrum,source&
pharmacologicalactivity.
Basedonthestructure
antibioticsareofdifferenttypes
like
βlactams,Aminoglycosides,
Tetracyclines,Macrolides,
polypeptides,Quinolines,Sulfa
antibiotics&miscellaneous.
PENICILLINScomesunderβ-
LACTAM
CLASSOFANTIBIOTICS.

• 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.

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.

 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.

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

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):
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

2.United states pharmacopoeia:
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

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.
N
S
CH3
CH3
COOH
H2N
HH
O
H
1
2
3
4
5
7
6
6-Amino penicillanic acid

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.

Basic structure of Penicillin:
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

 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.

STRUCTURALACTIVITY RELATIONSHIP :
1
2
3
4
56
7

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.
N
S
CH3
CH3
COOH
O
HNCH2C
O
H H
H

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.
N
S
CH3
CH3
COOH
O
HNCH2C
O
O
H H
H

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.
N
S
CH3
CH3
COOH
O
HNC
O
H H
H
CH3
CH3

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

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
N
S
CH3
CH3
COOH
O
HNC
H H
N
O
R1
R2
CH3
O
H

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.
N
S
CH3
CH3
COOH
O
HNC
H H
HC
O
H
NH2

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.
N
S
CH3
CH3
COOH
O
HNC
H H
HC
O
H
NH2
HO

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

Chemical degradation:
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

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

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

Enzymatic hydrolysis with Penicillinase or β lactamase:
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:

Synthesis of Penicillins from 6-APA:
 Production of 6-APA:
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

• Synthesis of Penicillin G from 6-APA:
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

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.
Mechanism of action: Gram +ve Gram -ve
Cell membrane
Peptidoglycon
cell wall
Lipopolysacc
haride layer

(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.

(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)

Beta lactamase Inhibitors:
 Has negligible antibacterial activity.
 Given with Penicillins which increases spectrum of activity.
 Microbial resistance to beta lactam antibiotics.
N
S
O
HN
S
O OH
Beta alctamase

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

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.
N
O
O
H
COOH
H
H
OH
N
S
O COO-Na+
H
O
CH3
CH3
O
H

Tazobactum:
 Co-administered with Piperacillin.
 Has little or no antibacterial activity.
N
S
O COO-
O CH3
O
H
N
N
N
Beta lactamase Inhibitors:
Available agents β-lactamase binding Potency
Clavulanic acid + + + + + +
Sulbactam + + + + + +
Tazobactam + + + + + + + +

Combinations of penicillins with β lactamase inhibitors:
Amoxicillin + Clavulanic acid = Clavulin
Ticarcillin + Clavulanic acid = Timentin
Piperacillin + Tazobactam = Tazocin
Ampicillin + Sulbactum = Unasyn

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.

 Ampicillin & Amoxycillin HELPS to clear Enterococci infections.
H- Heamophilus Influenzae
E- Escherichia coli
L- Listeria monocytogene
P- Proteus mirabilis
S- Salmonella typhi

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.

Hypersensitivity or Allergic reactions:
 Caused by degradation products of penicillin.
 3 types of hypersensitivity.
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

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.

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.

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.

 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.

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.

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

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

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