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Medicinal Chemistry of Antibiotic
Prepared By Ganesh D.Mote
AGCOP,Satara
Antibiotics
Defination-‘An antibiotic or an antibiotic substance is a substance
produced by the microorganisms, which has the capacity of
inhibiting the growth and even of destroying other micro-
organisms’
Classification of Antibiotics-
1. Β-lactamantibiotics:Penicillins,Cephalosporins,Monobactams, Carbapenems.
2. β-lactamase inhibitors—Clavulanic acid, Sulbactam,Tazobactum.
3. Tetracyclines: Oxytetracycline, Doxycycline, etc.
4. Nitrobenzene derivative: Chloramphenicol.
5. Aminoglycosides: Streptomycin, Gentamicin,Amikacin,Neomycin, etc.
6. Macrolide antibiotics: Erythromycin, Roxithromycin,Clarithromycin, Azithromycin.
7. Lincosamide antibiotics: Lincomycin, Clindamycin.
8. Polypeptide antibiotics: Polymyxin-B, Colistin,Bacitracin, Tyrothricin.
Classification of Penicillin
1. Acid-resistant alternative to penicillin G-Phenoxymethyl
penicillin (Penicillin V).
2. Penicillinase-resistant penicillins -Methicillin,Cloxacillin.
3. Extended spectrum penicillins
(a) Aminopenicillins:-Ampicillin, Bacampicillin,Amoxicillin.
(b) Carboxypenicillins: Carbenicillin, Ticarcillin.
(c) Ureidopenicillins: Piperacillin, Mezlocillin.
4.B-lactamase inhibitors -Clavulanic acid,Sulbactam,
Tazobactam
Classification of Cephalosporins
(1) Aminoglycosides bind to several sites at 30S and 50S subunits as well as to their interface-
freeze initiation, interfere with polysome formation and cause misreading of mANA code.
(2) Tetracyclines bind to 30S ribosome and inhibit aminoacyl tRNA attachment to the 'A' site.
(3) Chloramphenicol binds to 50S subunit-interferes with peptide bond formation and transfer of
peptide chain from 'P' site.
(4) Erythromycin and clindamycin also bind to 50S ribosome and hinder translocation of the
elongated peptide chain back from 'A' site to 'P' site and the ribosome does not move along the
mANA to expose the next codon. Peptide synthesis may be prematurely terminated.
MOA of Antibiotics
Penicillins
Structure of peniciilin and its derivatives
Structure of penicillin
Ampicillin
amoxicillin
B-lactamase inhibitor
Therapeutic classification of Cephalosporin
Generation Characteristics
First
generation
Poor serum and tissue concentrat ion
Not valuable for systemic infections
Lack activity against Pseudomonas aeruginosa,
Gram-positive organisms, and anaerobes
Second
generation
Adequate serum and tissue concentration
Good for systemic infections
Active against Gram-negative organisms, including P.
aeruginosa; weak activity against Streptococcus
pneumoniae; no activity against anaerobes
Third
generation
Once-daily dosing
Active against S. pneumoniae and atypical bacteria; less
active against P. aeruginosa
Fourth
generation
Active against anaerobes and aerobic
Gram-positive and Gram-negative organisms
First Generation of Cephalosporins
Second generation cephalosporin
cefaclor
Cefuroxime sodium
Cefoxitin sodium
Third generation cephalosporin
cefixime
cefotaxime
Cefpodoxime proxetil
Fourth Generation Cephalosporins
PENICILLINSPENICILLINS
N
S Me
Me
H
N
CO2H
O
C H H
O
R
INTRODUCTION TO PENICILLINSINTRODUCTION TO PENICILLINS
•Antibacterial agents which inhibit bacterial cell wall synthesis
•Discovered by Fleming from a fungal colony (1928)
•Shown to be non toxic and antibacterial
•Isolated and purified by Florey and Chain (1938)
•First successful clinical trial (1941)
•Produced by large scale fermentation (1944)
•Structure established by X-ray crystallography (1945)
•Full synthesis developed by Sheehan (1957)
•Isolation of 6-APA by Beechams (1958-60)
- development of semi-synthetic penicillins
•Discovery of clavulanic acid and β-lactamase inhibitors
STRUCTURESTRUCTURE
Side chain varies depending on carboxylic acid present in fermentation mediSide chain varies depending on carboxylic acid present in fermentation mediu
present in corn steep liquor
Penicillin GCH2 CO2H
Benzyl penicillin (Pen G)Benzyl penicillin (Pen G)
R =R =
Phenoxymethyl penicillin (Pen V)Phenoxymethyl penicillin (Pen V)
R =R =
CH2
O CH2
N
S Me
Me
H
N
H H
CO2H
O
C
O
R
Penicillin V
(first orally active penicillin)
OCH2 CO2H
Acyl sideAcyl side
chainchain
N
S Me
Me
H
N
H H
CO2H
O
C
O
R 6-Aminopenicillanic acid6-Aminopenicillanic acid
(6-APA)(6-APA)
Acyl sideAcyl side
chainchain
N
S Me
Me
H
N
H H
CO2H
O
C
O
R 6-Aminopenicillanic acid6-Aminopenicillanic acid
(6-APA)(6-APA)
Acyl sideAcyl side
chainchain
N
S Me
Me
H
N
H H
CO2H
O
C
O
R
ThiazolidineThiazolidine
ringring
6-Aminopenicillanic acid6-Aminopenicillanic acid
(6-APA)(6-APA)
Acyl sideAcyl side
chainchain
N
S Me
Me
H
N
H H
CO2H
O
C
O
R
ThiazolidineThiazolidine
ringring
β-Lactam
ring
Shape of Penicillin GShape of Penicillin G
Folded ‘envelope’ shapeFolded ‘envelope’ shape
H
NO
NH
C
O
R
H
S
CO2H
H
Me
Me
..
Biosynthesis of PenicillinsBiosynthesis of Penicillins
S
N
Me
Me
O
H
N
CO2H
C
R
O
CYSCYS
S
N
Me
Me
O
H
N
CO2H
C
R
O
VALVALCYSCYS
S
N
Me
Me
O
H
N
CO2H
C
R
O
Properties of Penicillin GProperties of Penicillin G
•Active vs. Gram +ve bacilli and some Gram -ve cocci
•Non toxic
•Limited range of activity
•Not orally active - must be injected
•Sensitive to β-lactamases
(enzymes which hydrolyse the β-lactam ring)
•Some patients are allergic
•Inactive vs. Staphylococci
Drug DevelopmentDrug Development
AimsAims
•To increase chemical stability for oral administration
•To increase resistance to β-lactamases
•To increase the range of activity
SARSAR
Conclusions
•Amide and carboxylic acid are involved in binding
•Carboxylic acid binds as the carboxylate ion
•Mechanism of action involves the β-lactam ring
•Activity related to β-lactam ring strain (subject to stability factors)
•Bicyclic system increases β-lactam ring strain
•Not much variation in structure is possible
•Variations are limited to the side chain (R)
Bicyclic systemessential
N
S Me
Me
H
N
CO2H
O
C H H
O
R
Carboxylic acid essential
Cis Stereochemistry essential
β−Lactam essential
Amide essential
•Penicillins inhibit a bacterial enzyme called the transpeptidase enzyme which is involved in
the synthesis of the bacterial cell wall
•The β-lactam ring is involved in the mechanism of inhibition
•Penicillin becomes covalently linked to the enzyme’s active site leading to irreversible
inhibition
•Covalent bond formed
to transpeptidase enzyme
•Irreversible inhibition
N
S Me
Me
H
N
H H
CO2H
O
C
O
R
Nu
Enz
C
H
N
C
CO2H
HH
Me
MeS
HN
O
R
O
Nu-Enz-H
N
S Me
Me
H
N
H H
CO2H
O
C
H
Enz-Nu
O
R
Mechanism of actionMechanism of action
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
L-Ala
D-Glu
L-Lys
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
NAM NAM NAMNAGNAG
NAM NAM NAMNAGNAG
NAM NAM NAMNAGNAG
Bond formation
inhibited by
penicillin
D-Alanine
TRANSPEPTIDASE
PENICILLIN
SUGAR
BACKBONE
NAM
L-Ala
NAG
D-Glu
L-Lys
D-Ala
D-Ala
Gly Gly Gly Gly Gly Gly GlyGlyGlyGlyL-Lys
NAG
D-Ala
D-Ala
D-Glu
L-Ala
NAM
SUGAR
BACKBONE
L-Lys Gly Gly
D-Ala
NAM
L-Ala
NAG
D-Glu
L-Lys Gly Gly Gly Gly GlyGlyGlyGly
NAG
D-Ala
D-Glu
L-Ala
NAM
Cross linkingCross linking
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
•Penicillin inhibits final crosslinking stage of cell wall synthesis
•It reacts with the transpeptidase enzyme to form an irreversible covalent bond
•Inhibition of transpeptidase leads to a weakened cell wall
•Cells swell due to water entering the cell, then burst (lysis)
•Penicillin possibly acts as an analogue of the L-Ala-γ-D-Glu portion of the pentapeptide
chain. However, the carboxylate group that is essential to penicillin activity is not present in
this portion
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
Gram +ve and Gram -ve Cell WallsGram +ve and Gram -ve Cell Walls
•Penicillins have to cross the bacterial cell wall in order to reach their target enzyme
•Cell walls are porous and are not a barrier
•The cell walls of Gram +ve bacteria are thicker than Gram -ve cell walls, but the former
are more susceptible to penicillins
Resistance to PenicillinsResistance to Penicillins
FactorsFactors
•Gram -ve bacteria have a lipopolysaccharide outer membrane preventing access to the
cell wall
•Penicillins can only cross via porins in the outer membrane
•Porins allow small hydrophilic molecules such as zwitterions to cross
•High levels of transpeptidase enzyme may be present
•The transpeptidase enzyme may have a low affinity for penicillins
(e.g. PBP 2a for S. aureus)
•Presence of β-lactamases
•Concentration of β-lactamases in periplasmic space
•Mutations
•Transfer of β-lactamases between strains
•Efflux mechanisms pumping penicillin out of periplasmic space
Penicillin Analogues - PreparationPenicillin Analogues - Preparation
1) By fermentation
•Vary the carboxylic acid in the fermentation medium
•Limited to unbranched acids at the α-position i.e. RCH2CO2H
•Tedious and slow
2) By total synthesis
•Only 1% overall yield
•Impractical
3) By semi-synthetic procedures
•Use a naturally occurring structure as the starting material for analogue synthesis
Penicillin Analogues - PreparationPenicillin Analogues - Preparation
Fermentation
Penicillin acylasePenicillin acylase
or chemical hydrolysisor chemical hydrolysis
O
C
ClR
Penicillin G
H
C
H
N
CO2H
O
Me
Me
N
S
O
CH2
6-APA
O
CO2H
HH
H2N
Me
MeS
N
Semi-synthetic penicillinsSemi-synthetic penicillins
N
S Me
Me
H
N
H H
CO2H
O
C
O
R
Penicillin Analogues - PreparationPenicillin Analogues - Preparation
ProblemProblem - How does one hydrolyse the side chain by chemical means in presence of a- How does one hydrolyse the side chain by chemical means in presence of a
labilelabile ββ-lactam ring?-lactam ring?
AnswerAnswer - Activate the side chain first to make it more reactive- Activate the side chain first to make it more reactive
NoteNote - Reaction with PCl- Reaction with PCl55 requires the involvement of a lone pair of electronsrequires the involvement of a lone pair of electrons
from nitrogen. Not possible for thefrom nitrogen. Not possible for the ββ-lactam nitrogen.-lactam nitrogen.
N
S
NH
O
CO2H
C
O
PhCH2
PCl5
PEN
NC
Cl
PhCH2
ROH
PEN
NC
OR
PhCH2
H2O
6-APA
Problems with Penicillin GProblems with Penicillin G
•It is sensitive to stomach acids
•It is sensitive to β-lactamases - enzymes which hydrolyse the β-lactam ring
• It has a limited range of activity
Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity
Reasons for sensitivityReasons for sensitivity
1) Ring strain1) Ring strain
H2O
H
N
S Me
Me
H
N
H H
CO2H
O
C
O
R
Relieves ring strainRelieves ring strain
C
H
N
HO2C
CO2H
HH
Me
MeS
HN
O
R
Acid or
enzyme
N
S Me
Me
H
N
H H
CO2H
O
C
HO
O
R
Problem 1 - SensitivityProblem 1 - Sensitivity
2) Reactive2) Reactive ββ-lactam carbonyl group-lactam carbonyl group
Does not behave like a tertiary amideDoes not behave like a tertiary amide
•Interaction of nitrogen’s lone pair with the carbonyl group is not possibleInteraction of nitrogen’s lone pair with the carbonyl group is not possible
•Results in a reactive carbonyl groupResults in a reactive carbonyl group
Tertiary amideTertiary amide
C
O
R
NR2 Unreactive
R
C
R
N
O
R
ββ-Lactam-Lactam
Folded ring
system
N
S
O
H
Me
Me
CO2H
Impossibly
strained
N
S
Me
Me
CO2H
O
Reasons for sensitivityReasons for sensitivity
X
Problem 1 - SensitivityProblem 1 - Sensitivity
Acyl side chain
Neighboring group participation in the hydrolysis mechanism
H
Further
reactions
-H
N
S
O
N
O
R R
O
N
O
S
HN
C N
O
S
N
H
R
O
H
Reasons for sensitivityReasons for sensitivity
C
E.W.G.
O
H
N
O
S
N
H
Problem 1 - SensitivityProblem 1 - Sensitivity
Conclusions
•The β-lactam ring is essential for activity and must be retained
•Cannot tackle factors 1 and 2
•Can only tackle factor 3
Strategy
Vary the acyl side group (R) to make it electron-withdrawing to decrease the
nucleophilicity of the carbonyl oxygen
Decreases
nucleophilicity
N
S
H
N
O
C
O
CH2PhO
H
Penicillin VPenicillin V
(orally active)(orally active)
Problem 1 - SensitivityProblem 1 - Sensitivity
Examples
electronegative
oxygen
Very successful semi-synthetic
penicillins
e.g. ampicillin, oxacillin
•Better acid stability and orally active
•But sensitive to β-lactamases
•Slightly less active than penicillin G
•Allergy problems with some patients
X = NH2, Cl, PhOCONH,
Heterocycles, CO2H
C
HC
O
H
N
O
S
N
X
R
Hα
Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases
ββ-Lactamases-Lactamases
•Enzymes that inactivate penicillins by opening β-lactam rings
•Allow bacteria to be resistant to penicillin
•Transferable between bacterial strains (i.e. bacteria can acquire resistance)
•Important with respect to Staphylococcus aureus infections in hospitals
•80% Staph. infections in hospitals were resistant to penicillin and other antibacterial agents
by 1960
•Mechanism of action for lactamases is identical to the mechanism of inhibition for the
target enzyme
• But product is removed efficiently from the lactamase active site
β-Lactamase
N
S Me
Me
H
N
CO2H
O
C
H
O
R
C
H
N
CO2H
Me
MeS
HN
H
HO2C
O
R
BulkyBulky
groupgroup
Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases
StrategyStrategy
EnzymeEnzyme
C
R
H
N
O
CO2H
Me
MeS
N
H H
O
•Use of steric shields
•Block access of penicillin to the active site of the enzyme by introducing bulky groups to the
side chain
•Size of shield is crucial to inhibit reaction of penicillins with β-lactamases, but not with the
target transpeptidase enzyme
Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases
ExamplesExamples - Methicillin (Beechams - 1960)- Methicillin (Beechams - 1960)
•Methoxy groups block access to β-lactamases but not to transpeptidases
•Binds less readily to transpeptidases compared to penicillin G
•Lower activity compared to Pen G against Pen G sensitive bacteria
•Poor activity vs. some streptococci
•Inactive vs. Gram -ve bacteria
•Poor range of activity
•Active against some penicillin G resistant strains (e.g. Staphylococcus)
•Acid sensitive since there is no electron-withdrawing group
•Orally inactive and must be injected
N
S Me
Me
H
N
CO2H
O
MeO
OMe
H HC
O
orthoortho groupsgroups
importantimportant
N
S Me
Me
H
N
CO2H
O
MeO
OMe
H HC
O
Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases
ExamplesExamples - Oxacillin- Oxacillin
•Orally active and acid resistant
•Resistant to β-lactamases
•Active vs. Staphylococcus aureus
•Less active than other penicillins
•Inactive vs. Gram -ve bacteria
•Nature of R & R’ influences absorption and plasma protein binding
•Cloxacillin better absorbed than oxacillin
•Flucloxacillin less bound to plasma protein, leading to higher levels of free d
Bulky and
e- withdrawing
Oxacillin R = R' = HOxacillin R = R' = H
Cloxacillin R = Cl, R' = HCloxacillin R = Cl, R' = H
Flucloxacillin R = Cl, R' = FFlucloxacillin R = Cl, R' = FN
O
C
O
H
N
O
CO2H
Me
MeS
N
R'
R
Me
H H
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Factors
1) Cell wall may have a coat preventing access to the cell
2) Excess transpeptidase enzyme may be present
3) Resistant transpeptidase enzyme (modified structure)
4) Presence of β-lactamases
5) Transfer of β-lactamases between strains
6) Efflux mechanisms
Strategy
•The number of factors involved make a single strategy impossible
•Use trial and error by varying R groups on the side chain
•Successful in producing broad spectrum antibiotics
•Results demonstrate general rules for broad spectrum activity.
Problem 3 - Range of ActivityProblem 3 - Range of Activity
1) Hydrophobic side chains result in high activity vs. Gram +ve bacteria and poor activity vs.
Gram -ve bacteria
2) Increasing hydrophobicity has little effect on Gram +ve activity
but lowers Gram -ve activity
3) Increasing hydrophilic character has little effect on Gram +ve activity
but increases Gram -ve activity
4) Hydrophilic groups at the α-position (e.g. NH2, OH, CO2H) increase activity vs Gram -ve
bacteria
Results of varying R in Pen GResults of varying R in Pen G
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Examples of Broad Spectrum PenicillinsExamples of Broad Spectrum Penicillins
Class 1 - NH2 at the α-position
Ampicillin and amoxicillin (Beechams, 1964)
Ampicillin (Penbritin)Ampicillin (Penbritin)
2nd most used penicillin2nd most used penicillin
Amoxicillin (Amoxil)Amoxicillin (Amoxil)
H
C
H
O
H
NC
NH2
HO
O
C
NH2
C
H
N
O
H
H
O
Problem 3 - Range of ActivityProblem 3 - Range of Activity
•Active vs Gram +ve bacteria and Gram -ve bacteria which do not produce β-lactamases
•Acid resistant and orally active
•Non toxic
•Sensitive to β-lactamases
•Increased polarity due to extra amino group
•Poor absorption through the gut wall
•Disruption of gut flora leading to diarrhea
•Inactive vs. Pseudomonas aeruginosa
Examples of Broad Spectrum PenicillinsExamples of Broad Spectrum Penicillins
Properties
O
N
H
NC
C
NH2
S Me
Me
CO2R
H H
H
O
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Prodrugs of AmpicillinProdrugs of Ampicillin (Leo Pharmaceuticals - 1969)(Leo Pharmaceuticals - 1969)
Properties
•Increased cell membrane permeability
•Polar carboxylic acid group is masked by the ester
•Ester is metabolised in the body by esterases to give the free drug
PIVAMPICILLINR = CH2O
C
O
CMe3
TALAMPICILLINR = O
O
BACAMPICILLIN
R = CH
Me
O
C
O
O CH2Me
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Mechanism of prodrug activationMechanism of prodrug activation
•Extended ester is less shielded by the penicillin nucleusExtended ester is less shielded by the penicillin nucleus
•Hydrolysed product is chemically unstable and degradesHydrolysed product is chemically unstable and degrades
•Methyl ester of ampicillin is not hydrolysed in the bodyMethyl ester of ampicillin is not hydrolysed in the body
•Bulky penicillin nucleus acts as a steric shield for methyl esterBulky penicillin nucleus acts as a steric shield for methyl ester
ENZYME
PEN
C O CH2
O
O
H
H
H
PEN
C O CH2
O
O
C
O
CMe3
FormaldehydeFormaldehyde
PEN
C OH
O
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Examples of broad spectrum penicillinsExamples of broad spectrum penicillins
Class 2 - CO2H at the α-position (carboxypenicillins)
Examples
•Carfecillin = prodrug for carbenicillin
•Active over a wider range of Gram -ve bacteria than ampicillin
•Active vs. Pseudomonas aeruginosa
•Resistant to most β-lactamases
•Less active vs Gram +ve bacteria (note the hydrophilic group)
•Acid sensitive and must be injected
•Stereochemistry at the α-position is important
•CO2H at the α-position is ionised at blood pH
R = H CarbenicillinR = H Carbenicillin
R = Ph CarfecillinR = Ph CarfecillinH H
O
N
H
NC
CH
CO2R
S Me
Me
CO2H
O
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Class 2 - CO2H at the α-position (carboxypenicillins)
Examples
•Administered by injection
•Identical antibacterial spectrum to carbenicillin
•Smaller doses required compared to carbenicillin
•More effective against P. aeruginosa
•Fewer side effects
•Can be administered with clavulanic acid
TICARCILLINTICARCILLIN
S
N
Me
Me
O
HH
CO2H
H
N
O
CO2H
S
Examples of broad spectrum penicillinsExamples of broad spectrum penicillins
Problem 3 - Range of ActivityProblem 3 - Range of Activity
Class 3 - Urea group at the α-position (ureidopenicillins)
Examples
•Administered by injection
•Generally more active than carboxypenicillins vs. streptococci and Haemophilus
species
•Generally have similar activity vs Gram -ve aerobic rods
•Generally more active vs other Gram -ve bacteria
•Azlocillin is effective vs P. aeruginosa
•Piperacillin can be administered alongside tazobactam
Azlocillin
Mezlocillin
Piperacillin
S
N
Me
Me
O
HH
CO2H
H
N
O
NH
O
R2N
HN
N
O
N
N
O
MeO2S
N N
OO
Et
Examples of broad spectrum penicillinsExamples of broad spectrum penicillins
SAR of cephalosporins
1. 7-Acylamino substituents:
a) Acylation of amino group generally increases the potency against gram-positive
bacteria, but it is accompanied by a decrease in gram-negative potency.
b) High antibacterial activity is observed only when the new acyl groups are derived
from carboxylic acids for gram-positive bacteria.
c) Substituents on the aromatic ring that increases lipophilicity provide higher
gram-positive activity and generally lower gram-negative activity.
d) The phenyl ring in the side-chain can be replaced with other heterocycles with
improved spectrum of activity and pharmacokinetic properties, and these
include thiophene, tetrazole, furan, pyridine, and aminothiazoles
2. C-3 substituents:The nature of C-3 substituents influences pharmacokinetic
and pharmacological properties as well as antibacterial activity. Modification at
C-3 position has been made to reduce the degradation (lactone of desacetyl
cephalosporin) of cephalosporins.
SAR of cephalosporins
3. Pyridine and imidazole-replaced acetoxy groups show improved activity
againstP.aeruginosa.Displacement of acetoxy group by azide ion yields derivatives with
relatively low gram-negative activity.
4. Displacement with aromatic thiols of 3-acetoxy group results in an enhancement of activity
against gram-negative bacteria with improved pharmacokinetic properties.
5. Replacement of acetoxy group at C-3 position with —CH3, Cl has resulted in orally active
compounds.
6. Oxidation of ring sulphur to sulphoxide or sulphone greatly diminishes or destroys the
antibacterial activity.
7. Replacement of sulphur with oxygen leads to oxacepam (latamoxef) with increased
antibacterial activity, because of its enhanced acylating power.
8. Similarly, replacement of sulphur with methylene group (loracarbef) has greater chemical
stability and a longer half-life.
9. The carboxyl group of position-4 has been converted into ester prodrugs to increase
bioavailability of cephalosporins, and these can be given orally as well. Examples include
cefuroxime axetil and cefodoxime proxetil
10. Olefinic linkage at C 3-4 is essential for antibacterial activity. Isomerization of the double
bond to 2-3 position leads to great losses in antibacterial activity.
Medicinal Chemistry of
Aminoglycoside Antibiotics
52
Introduction
 Antibiotics contain an aminocyclitol moiety to which
aminosugars are glycosidically linked.
 They may be more correctly called aminocyclitol
antibiotics.
O
O
O
O
H2C
NH2
H2N
OH
NH2
HO
NH2
HO
NH2
Tobramycin
HOH2C
HO
1
1''
2''3''4''
5''
1'
5'
4'
3' 2'
3
4
5 6
6'
2
6''
O
O
O
O
R1H2C
HO
HO
R2
H2N
OH
NH2
HOH2C
HO
NH2
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Kanamycins
53REVOLUTIOPHARMD.CO
M
Aminocyclitols???
 Cyclohexanes with several substituted or unsubstituted amino
and hydroxyl groups which bring them high water solubility.
 Streptidine and Streptamine can be called 1,3-diguanidino and
1,3-diamino inositol, respectively.
NH2
OH
HO
H2N
NH2
OH
HO
H2N
OH
H2N
HO
HO
HO
HO
OH
NHCH3
H3CO
1
2
3
45
6
1
2 3
4
56
1
2
345
6
H
N
OH
HO
HN
HO
OH1
2
3
45
6
NH
NH2
NH
H2N
Streptamine
Streptidine
2-Deoxystreptamine
NHCH3
OH
HO
1 2
3
4
56
OH
Spectinamine Fortamine
54REVOLUTIOPHARMD.CO
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 All have an aminohexose as the amino sugar and some
have a pentose as an extra sugar.
O
O
O
O
O
O
OH
CH2OH
H2N
NH2
HO
NH2
HO
HO
OH
HO
HO
R1
R2 NH2
Paromomycin I: R1= H; R2= CH2NH2
Paromomycin II: R1= CH2NH2; R2= H
1
2
3
34
5
6
1'
2'
3'
4'
5'
6'
12
3
44 5 1
2
55REVOLUTIOPHARMD.CO
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Spectrum of Antimicrobial Activity
 Aminoglycosides are broad-spectrum antibiotics
effective in:
1. Systemic Infections caused by aerobic G(-) bacillus
(klebsiella, proteus, enterobacters).
2. Tuberculosis, Brucellusis, Tularaemia and yersinia
infections.
3. Amoebic dysentery, shigellosis and salmonellosis.
4. Pneumonia and urinary infections caused by
Pseudomona aeroginosa.
 G(+) and G(-) aerobic cocci except staphylococci and
anaerobic bacteria are less susceptible.
56REVOLUTIOPHARMD.COM
Microbial Resistance against
Aminoglycosides
 Resistant strains have emerged against
streptomycin, kanamycin and gentamycin in
clinic.
 R factor is resposible for the production of
aminoglycoside deactivating enzymes:
1) Acetyl transferases (AAC)
2) Phosphotransferases (APH),
3) Nucleotidyl transferases (ANT)
 These enzymes transfer to hydroxyl and amino
groups of the drug.
57REVOLUTIOPHARMD.CO
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Aminoglycoside Deactivating Enzymes
• AAC acetylates 3-NH2of the ring II, and 2`, 6`- NH2 of the ring I.
• APH phosphorylates 3`-OHof the ring I and 2``-OH of the ring III.
• ANT adenylates 2``,4``-OH of the ring III and 4`-OH of the ring I.
O
O
O
O
OH
NH2
OH
H2N
OH
NH2
H2N
HO
H2N
HO
OH
1 2
3
45
6
1'
2'
4'
1''
3'
2''
5'
3''
5''
4''
6''
6'
I
II
III
ANT-4'
ANT-4''
ANT-2''
, APH-2''
AAC- 6'
AAC- 2'
APH- 3'
AAC- 3
Kanamycin B
58REVOLUTIOPHARMD.CO
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Gentamycin and Deactivating Enzymes
O
O
O
O
HC
NH2
H2N
OH
NH
H3C
NH2
HO
1''
2''3''4''
5''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Garosamine
2-Deoxystreptamine
Gentamicin C1: R1=R2 = CH3
Gentamicin C2: R1 = CH3 ; R2 = H
Gentamicin C1a: R1=R2 = H
OH
CH3
NHR2R1
Lack 3`-OH
APH Resistant
Axial and tertiary 4``-OH instead of
equatorial secondary 4``-OH in Kanamycin
ANT Resistant
Secondary amino group at 6`-NH2 in
Gentamycin C1, spacial hynderance
AAC Resisistant
I
II
III
59REVOLUTIOPHARMD.CO
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Kanamycin and Deactivatig Enzymes
O
O
O
O
R1H2C
HO
HO
R2
H2N
OH
NH2
HOH2C
HO
NH2
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Kanosamine
2-Deoxystreptamine
Kanamycin A: R1= NH2 ; R2 = OH
Kanamycin B: R1 = NH2 ; R2 = NH2
Kanamycin C: R1= OH; R2 = NH2
III
II
I
3`-deoxy derivative
APH Resistant
4`-deoxy derivative
ANT Resistant
60REVOLUTIOPHARMD.CO
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Amikacin and Dactivating Enzymes
• 1-N-L-(-)-amino-α-hydroxybutyric acid derivative of
kanamycin A. Susceptible only against the action of
AAC 6`-amino and ANT 4`-OH, resistant against all
other deactivating enzymes.
O
O
O
O
H2NH2C
HO
HO
OH
H2N
OH
NH2
HOH2C
HO
NH
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Amikacin, L-AHBA derivative of
Kanamycin A
C C
O
CH2 CH2 NH2
OH
H
2
2-Deoxystreptamine
Kanosamine
61
Tobramycin and Deactivating Enzymes
O
O
O
O
H2C
NH2
H2N
OH
NH2
HO
NH2
HO
NH2
2-Deoxystreptamine
Tobramycin
HOH2C
HO
1
1''
2''3''4''
5''
1'
5'
4'
3' 2'
3
4
5 6
6'
2
6''
Lack 3`-OH
APH Resistant
62REVOLUTIOPHARMD.CO
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The Minor Mechanism for Microbial
Resistance
Decreased uptake of the drug in some strains of
p. aeroginosa in hospital infections because of
blockade in the active transport of
aminoglycosides.
Aminoglycoside molecules attach through their
cationic groups to anionic portions of membrane
phospholipids of bacteria. Upon this attachment
the the ATP-dependent uptake occurs.
Bivalent cations such as Ca2+
and Mg2+
compete with
the drug in this process and antagonise them.
Anaerobic bacteria lack the ATP-dependent uptake
process, so they are resistant to aminoglycosides.63REVOLUTIOPHARMD.COM
SAR of Aminoglycosides
O
O
O
O
OH
NH2
OH
H2N
OH
NH2
H2N
HO
H2N
HO
OH
1 2
3
45
6
1'
2'
4'
1''
3'
2''
5'
3''
5''
4''
6''
6'
I
II
III
ANT-4'
ANT-4''
ANT-2''
, APH-2''
AAC- 6'
AAC- 2'
APH- 3'
AAC- 3
Kanamycin B
 Ring I is very necessary for broad-spectrum
antibacterial activity.
 2` and 6`-NH2 groups are specially important.
Exchanging of one of them in kanamycin B with hydroxyl
group decreases the activity (kanamycin A, C)
64REVOLUTIOPHARMD.CO
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SAR of ring I continued
Methylation of C-6` or 6`- NH2 doesn’t alter the
antibacterial activity, but increases the resistance
against AAC.
O
O
O
O
HC
NH2
H2N
OH
NH
H3C
NH2
HO
1''
2''3''4''
5''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Garosamine
2-Deoxystreptamine
Gentamicin C1: R1=R2 = CH3
Gentamicin C2: R1 = CH3 ; R2 = H
Gentamicin C1a: R1=R2 = H
OH
CH3
NHR2R1
Lack 3`-OH
APH Resistant
Axial and tertiary 4``-OH instead of
equatorial secondary 4``-OH in Kanamycin
ANT Resistant
Secondary amino group at 6`-NH2 in
Gentamycin C1, spacial hynderance
AAC Resisistant
I
II
III
65REVOLUTIOPHARMD.CO
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SAR of ring I continued
Omitting the 3`-OH and/or 4`-OH in kanamycin
doesn’t decrease the antibacterial activity but
increases the resistance against AAC: 3`,4`-
dideoxykanamycin B: Dibekacin.
The same is true for gentamicin.
O
O
O
O
R1H2C
HO
HO
R2
H2N
OH
NH2
HOH2C
HO
NH2
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Kanosamine
2-Deoxystreptamine
Kanamycin A: R1= NH2 ; R2 = OH
Kanamycin B: R1 = NH2 ; R2 = NH2
Kanamycin C: R1= OH; R2 = NH2
III
II
I
3`-deoxy derivative
APH Resistant
4`-deoxy derivative
ANT Resistant
66REVOLUTIOPHARMD.CO
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SAR of ring I continued
O
OH
H3C
NHCH3
OH
O
NHR
HO
O
O
NH2
CH2OH
H2N
16
2
4 3
5
1'
2'
3'
4'
1''
2''3''
5''
4''
5'
Sisomicin: R=H
Netilmicin: R=C2H5
Omitting the 3`-OH and 4`-OH and the addition of
a double bond between C-4` and C-5`has the
same effect.
67REVOLUTIOPHARMD.CO
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SAR of Aminoglycosides continued
O
O
O
O
H2NH2C
HO
HO
OH
H2N
OH
NH2
HOH2C
HO
NH
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Amikacin, L-AHBA derivative of
Kanamycin A
C C
O
CH2 CH2 NH2
OH
H
2
2-Deoxystreptamine
Kanosamine
Ring II is flexible toward changes. 1-NH2 in
kanamycin can be acylated and the antibacterial
activity remains almost unchanged , but resistance
against deactivating enzymes increases: Amikacin
68REVOLUTIOPHARMD.CO
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SAR of ring II continued
1-NH2ethylation of sisomycin saves the
antibacterial activity and increases the enzymatic
resistance: Netilmycin
O
OH
H3C
NHCH3
OH
O
NHR
HO
O
O
NH2
CH2OH
H2N
16
2
4 3
5
1'
2'
3'
4'
1''
2''3''
5''
4''
5'
Sisomicin: R=H
Netilmicin: R=C2H5
69REVOLUTIOPHARMD.CO
M
SAR of Aminoglycosides continued
O
O
O
O
HC
NH2
H2N
OH
NH
H3C
NH2
HO
1''
2''3''4''
5''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Garosamine
2-Deoxystreptamine
Gentamicin C1: R1=R2 = CH3
Gentamicin C2: R1 = CH3 ; R2 = H
Gentamicin C1a: R1=R2 = H
OH
CH3
NHR2R1
I
II
III
 Ring III functional groups are less sensitive to modifications:
 2``-deoxy gentamicins are less active than 2``-OH ones, but 2``-NH2
derivative (seldomycin) are very active.
 3``- NH2 can be primary or secondary.
 4``-OH can be axial or equatorial, the former is resistant against
the deactivating enzymes (ANT).
70REVOLUTIOPHARMD.CO
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Mechanism of Action of Aminoglycosides
Inhibition of protein biosynthesis initiation upon
attachment to 30s portion of ribosomes.
Misreading mutation of the genetic code and the
synthesis of nonesense proteins which are not
normal proteins so they cannot take part in
cellular activities.
Nonesense proteins disturb the semipermeability
of the bacterial cell and aminoglycoside
molecules enter the cell easily and kill it.
71REVOLUTIOPHARMD.COM
Therapeutic Agents
Kanamycin
O
O
O
O
R1H2C
HO
HO
R2
H2N
OH
NH2
HOH2C
HO
NH2
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Kanosamine
2-Deoxystreptamine
Kanamycin A: R1= NH2 ; R2 = OH
Kanamycin B: R1 = NH2 ; R2 = NH2
Kanamycin C: R1= OH; R2 = NH2
III
II
I
 Isolated from cultures of Streptomyces kanamyceticus. The least
toxic member in the market is kanamycin A.
 It is used for the treatment of GI infections, such as dysentery and
systemic G(-) bacillus infections caused by klebsiella, proteus,
enterobacters.
 For disinfection of GI before an operation.
72REVOLUTIOPHARMD.CO
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Amikacin
O
O
O
O
H2NH2C
HO
HO
OH
H2N
OH
NH2
HOH2C
HO
NH
HO
1''
2''3''4''
5''6''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Amikacin
C C
O
CH2 CH2 NH2
OH
H
2
2-Deoxystreptamine
Kanosamine
A semisynthetic derivative of kanamycin A.
It is used in the treatment of infections caused by
Mycobacterium tuberculosis, Yersinia tularensis,
Pseudomona aeroginosa.
The suffix “micin” denotes its origin.
73REVOLUTIOPHARMD.CO
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Tobramycin
• Isolated from cultures of Streptomyces tenebrarius.
• Antimicrobial activity against resistance P.aeroginosa.
O
O
O
O
H2C
NH2
H2N
OH
NH2
HO
NH2
HO
2-Deoxystreptamine
Tobramycin
HOH2C
HO
1
1''
2''3''4''
5''
1'
5'
4'
3' 2'
3
4
5 6
2
6''
Lacks 3`-OH
APH Resistant
74REVOLUTIOPHARMD.CO
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Gentamicin
 Isolated from cultures of Micromonospora purpurea.
 The suffix “micin” denotes its origin.
 It is used against urinary infections caused by G(-) and
pseudomona.
O
O
O
O
HC
NH2
H2N
OH
NH
H3C
NH2
HO
1''
2''3''4''
5''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Garosamine
2-Deoxystreptamine
Gentamicin C1: R1=R2 = CH3
Gentamicin C2: R1 = CH3 ; R2 = H
Gentamicin C1a: R1=R2 = H
OH
CH3
NHR2R1
Lacks 3`-OH
APH Resistant
Axial and tertiary 4``-OH instead of
equatorial secondary 4``-OH in Kanamycin
ANT Resistant
Secondary amino group at 6`-NH2 in
Gentamycin C1, spacial hynderance
AAC Resisistant
I
II
III
75REVOLUTIOPHARMD.CO
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Neomycin
O
O
O
O
O
O
OH
CH2OH
H2N
NH2
HO
NH2
HO
HO
NH2
HO
HO
H2NH2C
R2 NH2
2-Deoxystreptamine
Neosamine C
Neosamine C
1
2
3
34
5
6
1'
2'
3'
4'
5'
6'
12
3
44 5 1
2
D-Ribose
Neomycin
Isolated from cultures of Streptomyces fradia along
with an antifungal subsance: Fradicin.
Effective against GI and dermal infections.
76REVOLUTIOPHARMD.CO
M
Netilmicin
O
OH
H3C
NHCH3
OH
O
NHR
HO
O
O
NH2
CH2OH
H2N
16
2
4 3
5
1'
2'
3'
4'
1''
2''3''
5''
4''
5'
Sisomicin: R=H
Netilmicin: R=C2H5
 A semisynthetic ethyl derivative of sisomicin isolated from
Micromonospora inyoensis.
 Ethylation causes spacial hynderance against APH and ATN
enzymes.
 Against gentamicin resistant pseudomona and proteus.
77REVOLUTIOPHARMD.CO
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Streptomycin
O
O
H
N
HO
OH
OH
NH
NH
H2N
OHO
H3C
CHO
O NHCH3
OH
HO
HO
H2N
HN
Streptidine
L-Streptose
N- Methyl-L-Glucosamine
Streptomycin
1''
2'3'
4'
12
3 4
1'
2''3''
4''
5''
6
5
 Has a different aminocyclito (a 1,3-diguanidinoinositol).
78REVOLUTIOPHARMD.CO
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Streptomycin continued
Isolated from cultures of Streptomyces griseus.
It was introduced against tuberculosis in 1943,
kanamycin and amikacin are effective against
tuberculosis, but not as much as streptomycin.
Streptomycin brought Waxman the Noble prize in
1952.
79REVOLUTIOPHARMD.COM
Mechanism of Chemical incompatility of
Aminoglycosides with β-lactams
Acylation of
aminocyclitol portion
by the β-lactam
molecule.
Begins with
nucleophilic addition
of the amino group to
the carbonyl group of
β-lactam ring.
N
O
NHCOR
HOOC
O
NHCOR
HN
HO
O
O
SUGAR
NH2
N
SUGAR
HOOC
H2N
HO
O
O
SUGAR
NH2
SUGAR
80REVOLUTIOPHARMD.CO
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Tetracyclines
• The tetracyclines are primarily bacteriostatic;
inhibit protein synthesis by binding to 305
ribosomes in susceptible organism.
• Subsequent to such binding, attachment of
aminoacyl-t-RNA to the mRNA-ribosome
complex is interferred.
• As a result,the peptide chain fails to grow.
Classification of tetracycline
medicinal chemistry of Antibiotic
SAR of tetracyclin
1. C-1 substituents: The keto-enol system of the A-ring is indispensable for antibacterial activity.
No variation at the C-1 position has been successful.
2. C-2 substituents: The carboxamide moiety is present in all naturally occurring tetracyclines
and this group is crucial for antibacterial activity. The amide is best left unsubstituted, or
mono-substitution is acceptable in the form of activated
3. C-3 substituents: In conjugation with the C-1 position, the keto-enol conjugated system is
imperative for antibacterial activity.
4. C-4 substituents: The naturally occurring tetracyclines contain α-C-4 dimethylamino
substituent that favourably contributes to the keto-enolic character of the A-ring.
Replacement of dimethylamino group with a hydrazone, oxime, or hydroxyl group leads to a
pronounced loss of activity, probably due to the increase in heteroatom basicity.
5. C-4a substituents: The α-hydrogen at C-4a position of tetracyclines is necessary for useful
antibacterial activity.
6. C-5 substituents: Many naturally occurring antibacterial tetracyclines have an unsubstituted
methylene moiety at the C-5 position. However, oxytetracycline contains C-5 α-hydroxyl
group and was found to be a potent compound, and has been modified chemically to some
semi-synthetic tetracyclines. Alkylation of the C-5 hydroxyl group results in a loss of activity.
Effect of pH on
tetracyclines
• An interesting property of tetracyclines is their ability to undergo epimerization at
C-4 in solutions of intermediate pH range. These isomers are called
epitetracyclines. Under the influence of the acidic conditions, an equilibrium is
established in about one day consisting of approximately equal amount of
isomers. Epitetracyclines exhibit much less activity than natural isomers.
• Strong acids and bases attack the tetracyclines having a hydroxyl group on C-6,
causing a loss in activity through modification of C-ring.
• Strong acids produce dehydration through a reaction involving the C-6 hydroxyl
group and C-5a hydrogen.
• Bases promote a reaction between the C-6 hydroxyl group and the ketone group
at the C-11 position, causing the bond between the C-11 and C-11a atoms to
cleave and to form the lactone ring found in the inactive isotetracycline.
SAR of tetracyclin
7. C-5a substituents: The configuration of the naturally occurring tetracyclines places the C-5a
hydrogen atom in an α-configuration. Epimerization is detrimental to antibacterial activity.
8. C-6 substituents:
The C-6 position is tolerant of a variety of substituents. The majority of tetracyclines have an α-methyl
group and a β-hydroxyl group at this position.
Demeclocyclin is a naturally occurring C-6 demethylated chlortetracycline with an excellent activity. This
C-6 methyl group contributes little to the activity of tetracycline.
Similarly, the C-6 hydroxyl group also appears to offer little in terms of antibacterial activity; removal of
this group affords doxycycline, which is a superb antibacterial.
9. C-7 and C-9 substituents:
The nature of the aromatic D-ring predisposes the C-7 position to electrophilic substitution, and nitro and
halogen groups have been introduced.
10. The C-7 acetoxy, azido, and hydroxyl tetracyclines are inferior in terms of antibacterial activity.
11. C-10 substituents: The C-10 phenolic moiety is absolutely necessary for antibacterial activity.
12. C-11 substituents: The C-11 carbonyl moiety is part of one of the conjugated keto-enol systems
required for antibacterial activity.
13. C-12a substituents: The C-12a hydroxyl group is needed for antibacterial activity, although this
Chloramphenicol
• MOA of Chloramphenicol-it inhibits bacterial
protein synthesis by interferring with
'transfer' of the elongating peptide chain to
the newly attached aminoacyl-tRNA at the
ribosome-mRNA complex.
• It specifically attaches to the 50S ribosome
and thus may hinder the access of aminoacyl-
tRNA to the acceptor site for amino acid
incorporation
• it prevents formation of peptide bonds
Microlide antibiotics
• MACROLIDE ANTIBIOTICS-The macrolide antibiotics have
three common chemical characteristics:
• A large lactone ring
• A ketone group
• A glycosidically linked amino sugar
• These are antibiotics having a macrocyclic lactone ring with
attached sugars.
• Among the many antibiotics isolated from the actinomycetes
is the group of chemically related compounds called the
macrolides
• Erythromycin is the first member discovered in the
1950s,Roxithromycin, Clarithromycin and Azithromycin.
Microlide structures
Erythromycin Clarithromycin
Azithromycin
SAR of Microlide
• A number of strategies have been utilized to
improve the acid stability of erythromycin.
• The first approach involved the addition of
hydroxylamine to the ketone to form oxime— e.g.,
roxithromycin.
• The second approach involves an alteration of C-6
hydroxyl group, which is the nucleophilic
functionality that initiates erythromycin
degradation. Modification that removes the
nucleophilic nature of this hydroxyl group can retain
antibacterial properties if the size of the group is
kept small so as not to affect the ribosomal binding
—e.g., clarithromycin.
• The azalides (e.g., azithromycin) are semi-synthetic
15-membered congeners in which a nitrogen atom
has been introduced to expand a 14-membered
precursor, and this leads to an extended spectrum
of action.
Lincomycin
Lincomycin Hydrocholride
Clindamycin

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medicinal chemistry of Antibiotic

  • 1. Medicinal Chemistry of Antibiotic Prepared By Ganesh D.Mote AGCOP,Satara
  • 2. Antibiotics Defination-‘An antibiotic or an antibiotic substance is a substance produced by the microorganisms, which has the capacity of inhibiting the growth and even of destroying other micro- organisms’ Classification of Antibiotics- 1. Β-lactamantibiotics:Penicillins,Cephalosporins,Monobactams, Carbapenems. 2. β-lactamase inhibitors—Clavulanic acid, Sulbactam,Tazobactum. 3. Tetracyclines: Oxytetracycline, Doxycycline, etc. 4. Nitrobenzene derivative: Chloramphenicol. 5. Aminoglycosides: Streptomycin, Gentamicin,Amikacin,Neomycin, etc. 6. Macrolide antibiotics: Erythromycin, Roxithromycin,Clarithromycin, Azithromycin. 7. Lincosamide antibiotics: Lincomycin, Clindamycin. 8. Polypeptide antibiotics: Polymyxin-B, Colistin,Bacitracin, Tyrothricin.
  • 3. Classification of Penicillin 1. Acid-resistant alternative to penicillin G-Phenoxymethyl penicillin (Penicillin V). 2. Penicillinase-resistant penicillins -Methicillin,Cloxacillin. 3. Extended spectrum penicillins (a) Aminopenicillins:-Ampicillin, Bacampicillin,Amoxicillin. (b) Carboxypenicillins: Carbenicillin, Ticarcillin. (c) Ureidopenicillins: Piperacillin, Mezlocillin. 4.B-lactamase inhibitors -Clavulanic acid,Sulbactam, Tazobactam
  • 5. (1) Aminoglycosides bind to several sites at 30S and 50S subunits as well as to their interface- freeze initiation, interfere with polysome formation and cause misreading of mANA code. (2) Tetracyclines bind to 30S ribosome and inhibit aminoacyl tRNA attachment to the 'A' site. (3) Chloramphenicol binds to 50S subunit-interferes with peptide bond formation and transfer of peptide chain from 'P' site. (4) Erythromycin and clindamycin also bind to 50S ribosome and hinder translocation of the elongated peptide chain back from 'A' site to 'P' site and the ribosome does not move along the mANA to expose the next codon. Peptide synthesis may be prematurely terminated. MOA of Antibiotics
  • 7. Structure of peniciilin and its derivatives
  • 10. Therapeutic classification of Cephalosporin Generation Characteristics First generation Poor serum and tissue concentrat ion Not valuable for systemic infections Lack activity against Pseudomonas aeruginosa, Gram-positive organisms, and anaerobes Second generation Adequate serum and tissue concentration Good for systemic infections Active against Gram-negative organisms, including P. aeruginosa; weak activity against Streptococcus pneumoniae; no activity against anaerobes Third generation Once-daily dosing Active against S. pneumoniae and atypical bacteria; less active against P. aeruginosa Fourth generation Active against anaerobes and aerobic Gram-positive and Gram-negative organisms
  • 11. First Generation of Cephalosporins
  • 16. INTRODUCTION TO PENICILLINSINTRODUCTION TO PENICILLINS •Antibacterial agents which inhibit bacterial cell wall synthesis •Discovered by Fleming from a fungal colony (1928) •Shown to be non toxic and antibacterial •Isolated and purified by Florey and Chain (1938) •First successful clinical trial (1941) •Produced by large scale fermentation (1944) •Structure established by X-ray crystallography (1945) •Full synthesis developed by Sheehan (1957) •Isolation of 6-APA by Beechams (1958-60) - development of semi-synthetic penicillins •Discovery of clavulanic acid and β-lactamase inhibitors
  • 17. STRUCTURESTRUCTURE Side chain varies depending on carboxylic acid present in fermentation mediSide chain varies depending on carboxylic acid present in fermentation mediu present in corn steep liquor Penicillin GCH2 CO2H Benzyl penicillin (Pen G)Benzyl penicillin (Pen G) R =R = Phenoxymethyl penicillin (Pen V)Phenoxymethyl penicillin (Pen V) R =R = CH2 O CH2 N S Me Me H N H H CO2H O C O R Penicillin V (first orally active penicillin) OCH2 CO2H Acyl sideAcyl side chainchain N S Me Me H N H H CO2H O C O R 6-Aminopenicillanic acid6-Aminopenicillanic acid (6-APA)(6-APA) Acyl sideAcyl side chainchain N S Me Me H N H H CO2H O C O R 6-Aminopenicillanic acid6-Aminopenicillanic acid (6-APA)(6-APA) Acyl sideAcyl side chainchain N S Me Me H N H H CO2H O C O R ThiazolidineThiazolidine ringring 6-Aminopenicillanic acid6-Aminopenicillanic acid (6-APA)(6-APA) Acyl sideAcyl side chainchain N S Me Me H N H H CO2H O C O R ThiazolidineThiazolidine ringring β-Lactam ring
  • 18. Shape of Penicillin GShape of Penicillin G Folded ‘envelope’ shapeFolded ‘envelope’ shape H NO NH C O R H S CO2H H Me Me ..
  • 19. Biosynthesis of PenicillinsBiosynthesis of Penicillins S N Me Me O H N CO2H C R O CYSCYS S N Me Me O H N CO2H C R O VALVALCYSCYS S N Me Me O H N CO2H C R O
  • 20. Properties of Penicillin GProperties of Penicillin G •Active vs. Gram +ve bacilli and some Gram -ve cocci •Non toxic •Limited range of activity •Not orally active - must be injected •Sensitive to β-lactamases (enzymes which hydrolyse the β-lactam ring) •Some patients are allergic •Inactive vs. Staphylococci Drug DevelopmentDrug Development AimsAims •To increase chemical stability for oral administration •To increase resistance to β-lactamases •To increase the range of activity
  • 21. SARSAR Conclusions •Amide and carboxylic acid are involved in binding •Carboxylic acid binds as the carboxylate ion •Mechanism of action involves the β-lactam ring •Activity related to β-lactam ring strain (subject to stability factors) •Bicyclic system increases β-lactam ring strain •Not much variation in structure is possible •Variations are limited to the side chain (R) Bicyclic systemessential N S Me Me H N CO2H O C H H O R Carboxylic acid essential Cis Stereochemistry essential β−Lactam essential Amide essential
  • 22. •Penicillins inhibit a bacterial enzyme called the transpeptidase enzyme which is involved in the synthesis of the bacterial cell wall •The β-lactam ring is involved in the mechanism of inhibition •Penicillin becomes covalently linked to the enzyme’s active site leading to irreversible inhibition •Covalent bond formed to transpeptidase enzyme •Irreversible inhibition N S Me Me H N H H CO2H O C O R Nu Enz C H N C CO2H HH Me MeS HN O R O Nu-Enz-H N S Me Me H N H H CO2H O C H Enz-Nu O R Mechanism of actionMechanism of action
  • 23. L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys L-Ala D-Glu L-Lys Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis NAM NAM NAMNAGNAG NAM NAM NAMNAGNAG NAM NAM NAMNAGNAG Bond formation inhibited by penicillin
  • 24. D-Alanine TRANSPEPTIDASE PENICILLIN SUGAR BACKBONE NAM L-Ala NAG D-Glu L-Lys D-Ala D-Ala Gly Gly Gly Gly Gly Gly GlyGlyGlyGlyL-Lys NAG D-Ala D-Ala D-Glu L-Ala NAM SUGAR BACKBONE L-Lys Gly Gly D-Ala NAM L-Ala NAG D-Glu L-Lys Gly Gly Gly Gly GlyGlyGlyGly NAG D-Ala D-Glu L-Ala NAM Cross linkingCross linking Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
  • 25. •Penicillin inhibits final crosslinking stage of cell wall synthesis •It reacts with the transpeptidase enzyme to form an irreversible covalent bond •Inhibition of transpeptidase leads to a weakened cell wall •Cells swell due to water entering the cell, then burst (lysis) •Penicillin possibly acts as an analogue of the L-Ala-γ-D-Glu portion of the pentapeptide chain. However, the carboxylate group that is essential to penicillin activity is not present in this portion Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
  • 26. Gram +ve and Gram -ve Cell WallsGram +ve and Gram -ve Cell Walls •Penicillins have to cross the bacterial cell wall in order to reach their target enzyme •Cell walls are porous and are not a barrier •The cell walls of Gram +ve bacteria are thicker than Gram -ve cell walls, but the former are more susceptible to penicillins
  • 27. Resistance to PenicillinsResistance to Penicillins FactorsFactors •Gram -ve bacteria have a lipopolysaccharide outer membrane preventing access to the cell wall •Penicillins can only cross via porins in the outer membrane •Porins allow small hydrophilic molecules such as zwitterions to cross •High levels of transpeptidase enzyme may be present •The transpeptidase enzyme may have a low affinity for penicillins (e.g. PBP 2a for S. aureus) •Presence of β-lactamases •Concentration of β-lactamases in periplasmic space •Mutations •Transfer of β-lactamases between strains •Efflux mechanisms pumping penicillin out of periplasmic space
  • 28. Penicillin Analogues - PreparationPenicillin Analogues - Preparation 1) By fermentation •Vary the carboxylic acid in the fermentation medium •Limited to unbranched acids at the α-position i.e. RCH2CO2H •Tedious and slow 2) By total synthesis •Only 1% overall yield •Impractical 3) By semi-synthetic procedures •Use a naturally occurring structure as the starting material for analogue synthesis
  • 29. Penicillin Analogues - PreparationPenicillin Analogues - Preparation Fermentation Penicillin acylasePenicillin acylase or chemical hydrolysisor chemical hydrolysis O C ClR Penicillin G H C H N CO2H O Me Me N S O CH2 6-APA O CO2H HH H2N Me MeS N Semi-synthetic penicillinsSemi-synthetic penicillins N S Me Me H N H H CO2H O C O R
  • 30. Penicillin Analogues - PreparationPenicillin Analogues - Preparation ProblemProblem - How does one hydrolyse the side chain by chemical means in presence of a- How does one hydrolyse the side chain by chemical means in presence of a labilelabile ββ-lactam ring?-lactam ring? AnswerAnswer - Activate the side chain first to make it more reactive- Activate the side chain first to make it more reactive NoteNote - Reaction with PCl- Reaction with PCl55 requires the involvement of a lone pair of electronsrequires the involvement of a lone pair of electrons from nitrogen. Not possible for thefrom nitrogen. Not possible for the ββ-lactam nitrogen.-lactam nitrogen. N S NH O CO2H C O PhCH2 PCl5 PEN NC Cl PhCH2 ROH PEN NC OR PhCH2 H2O 6-APA
  • 31. Problems with Penicillin GProblems with Penicillin G •It is sensitive to stomach acids •It is sensitive to β-lactamases - enzymes which hydrolyse the β-lactam ring • It has a limited range of activity
  • 32. Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity Reasons for sensitivityReasons for sensitivity 1) Ring strain1) Ring strain H2O H N S Me Me H N H H CO2H O C O R Relieves ring strainRelieves ring strain C H N HO2C CO2H HH Me MeS HN O R Acid or enzyme N S Me Me H N H H CO2H O C HO O R
  • 33. Problem 1 - SensitivityProblem 1 - Sensitivity 2) Reactive2) Reactive ββ-lactam carbonyl group-lactam carbonyl group Does not behave like a tertiary amideDoes not behave like a tertiary amide •Interaction of nitrogen’s lone pair with the carbonyl group is not possibleInteraction of nitrogen’s lone pair with the carbonyl group is not possible •Results in a reactive carbonyl groupResults in a reactive carbonyl group Tertiary amideTertiary amide C O R NR2 Unreactive R C R N O R ββ-Lactam-Lactam Folded ring system N S O H Me Me CO2H Impossibly strained N S Me Me CO2H O Reasons for sensitivityReasons for sensitivity X
  • 34. Problem 1 - SensitivityProblem 1 - Sensitivity Acyl side chain Neighboring group participation in the hydrolysis mechanism H Further reactions -H N S O N O R R O N O S HN C N O S N H R O H Reasons for sensitivityReasons for sensitivity
  • 35. C E.W.G. O H N O S N H Problem 1 - SensitivityProblem 1 - Sensitivity Conclusions •The β-lactam ring is essential for activity and must be retained •Cannot tackle factors 1 and 2 •Can only tackle factor 3 Strategy Vary the acyl side group (R) to make it electron-withdrawing to decrease the nucleophilicity of the carbonyl oxygen Decreases nucleophilicity
  • 36. N S H N O C O CH2PhO H Penicillin VPenicillin V (orally active)(orally active) Problem 1 - SensitivityProblem 1 - Sensitivity Examples electronegative oxygen Very successful semi-synthetic penicillins e.g. ampicillin, oxacillin •Better acid stability and orally active •But sensitive to β-lactamases •Slightly less active than penicillin G •Allergy problems with some patients X = NH2, Cl, PhOCONH, Heterocycles, CO2H C HC O H N O S N X R Hα
  • 37. Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases ββ-Lactamases-Lactamases •Enzymes that inactivate penicillins by opening β-lactam rings •Allow bacteria to be resistant to penicillin •Transferable between bacterial strains (i.e. bacteria can acquire resistance) •Important with respect to Staphylococcus aureus infections in hospitals •80% Staph. infections in hospitals were resistant to penicillin and other antibacterial agents by 1960 •Mechanism of action for lactamases is identical to the mechanism of inhibition for the target enzyme • But product is removed efficiently from the lactamase active site β-Lactamase N S Me Me H N CO2H O C H O R C H N CO2H Me MeS HN H HO2C O R
  • 38. BulkyBulky groupgroup Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases StrategyStrategy EnzymeEnzyme C R H N O CO2H Me MeS N H H O •Use of steric shields •Block access of penicillin to the active site of the enzyme by introducing bulky groups to the side chain •Size of shield is crucial to inhibit reaction of penicillins with β-lactamases, but not with the target transpeptidase enzyme
  • 39. Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases ExamplesExamples - Methicillin (Beechams - 1960)- Methicillin (Beechams - 1960) •Methoxy groups block access to β-lactamases but not to transpeptidases •Binds less readily to transpeptidases compared to penicillin G •Lower activity compared to Pen G against Pen G sensitive bacteria •Poor activity vs. some streptococci •Inactive vs. Gram -ve bacteria •Poor range of activity •Active against some penicillin G resistant strains (e.g. Staphylococcus) •Acid sensitive since there is no electron-withdrawing group •Orally inactive and must be injected N S Me Me H N CO2H O MeO OMe H HC O orthoortho groupsgroups importantimportant N S Me Me H N CO2H O MeO OMe H HC O
  • 40. Problem 2 - Sensitivity toProblem 2 - Sensitivity to ββ-Lactamases-Lactamases ExamplesExamples - Oxacillin- Oxacillin •Orally active and acid resistant •Resistant to β-lactamases •Active vs. Staphylococcus aureus •Less active than other penicillins •Inactive vs. Gram -ve bacteria •Nature of R & R’ influences absorption and plasma protein binding •Cloxacillin better absorbed than oxacillin •Flucloxacillin less bound to plasma protein, leading to higher levels of free d Bulky and e- withdrawing Oxacillin R = R' = HOxacillin R = R' = H Cloxacillin R = Cl, R' = HCloxacillin R = Cl, R' = H Flucloxacillin R = Cl, R' = FFlucloxacillin R = Cl, R' = FN O C O H N O CO2H Me MeS N R' R Me H H
  • 41. Problem 3 - Range of ActivityProblem 3 - Range of Activity Factors 1) Cell wall may have a coat preventing access to the cell 2) Excess transpeptidase enzyme may be present 3) Resistant transpeptidase enzyme (modified structure) 4) Presence of β-lactamases 5) Transfer of β-lactamases between strains 6) Efflux mechanisms Strategy •The number of factors involved make a single strategy impossible •Use trial and error by varying R groups on the side chain •Successful in producing broad spectrum antibiotics •Results demonstrate general rules for broad spectrum activity.
  • 42. Problem 3 - Range of ActivityProblem 3 - Range of Activity 1) Hydrophobic side chains result in high activity vs. Gram +ve bacteria and poor activity vs. Gram -ve bacteria 2) Increasing hydrophobicity has little effect on Gram +ve activity but lowers Gram -ve activity 3) Increasing hydrophilic character has little effect on Gram +ve activity but increases Gram -ve activity 4) Hydrophilic groups at the α-position (e.g. NH2, OH, CO2H) increase activity vs Gram -ve bacteria Results of varying R in Pen GResults of varying R in Pen G
  • 43. Problem 3 - Range of ActivityProblem 3 - Range of Activity Examples of Broad Spectrum PenicillinsExamples of Broad Spectrum Penicillins Class 1 - NH2 at the α-position Ampicillin and amoxicillin (Beechams, 1964) Ampicillin (Penbritin)Ampicillin (Penbritin) 2nd most used penicillin2nd most used penicillin Amoxicillin (Amoxil)Amoxicillin (Amoxil) H C H O H NC NH2 HO O C NH2 C H N O H H O
  • 44. Problem 3 - Range of ActivityProblem 3 - Range of Activity •Active vs Gram +ve bacteria and Gram -ve bacteria which do not produce β-lactamases •Acid resistant and orally active •Non toxic •Sensitive to β-lactamases •Increased polarity due to extra amino group •Poor absorption through the gut wall •Disruption of gut flora leading to diarrhea •Inactive vs. Pseudomonas aeruginosa Examples of Broad Spectrum PenicillinsExamples of Broad Spectrum Penicillins Properties
  • 45. O N H NC C NH2 S Me Me CO2R H H H O Problem 3 - Range of ActivityProblem 3 - Range of Activity Prodrugs of AmpicillinProdrugs of Ampicillin (Leo Pharmaceuticals - 1969)(Leo Pharmaceuticals - 1969) Properties •Increased cell membrane permeability •Polar carboxylic acid group is masked by the ester •Ester is metabolised in the body by esterases to give the free drug PIVAMPICILLINR = CH2O C O CMe3 TALAMPICILLINR = O O BACAMPICILLIN R = CH Me O C O O CH2Me
  • 46. Problem 3 - Range of ActivityProblem 3 - Range of Activity Mechanism of prodrug activationMechanism of prodrug activation •Extended ester is less shielded by the penicillin nucleusExtended ester is less shielded by the penicillin nucleus •Hydrolysed product is chemically unstable and degradesHydrolysed product is chemically unstable and degrades •Methyl ester of ampicillin is not hydrolysed in the bodyMethyl ester of ampicillin is not hydrolysed in the body •Bulky penicillin nucleus acts as a steric shield for methyl esterBulky penicillin nucleus acts as a steric shield for methyl ester ENZYME PEN C O CH2 O O H H H PEN C O CH2 O O C O CMe3 FormaldehydeFormaldehyde PEN C OH O
  • 47. Problem 3 - Range of ActivityProblem 3 - Range of Activity Examples of broad spectrum penicillinsExamples of broad spectrum penicillins Class 2 - CO2H at the α-position (carboxypenicillins) Examples •Carfecillin = prodrug for carbenicillin •Active over a wider range of Gram -ve bacteria than ampicillin •Active vs. Pseudomonas aeruginosa •Resistant to most β-lactamases •Less active vs Gram +ve bacteria (note the hydrophilic group) •Acid sensitive and must be injected •Stereochemistry at the α-position is important •CO2H at the α-position is ionised at blood pH R = H CarbenicillinR = H Carbenicillin R = Ph CarfecillinR = Ph CarfecillinH H O N H NC CH CO2R S Me Me CO2H O
  • 48. Problem 3 - Range of ActivityProblem 3 - Range of Activity Class 2 - CO2H at the α-position (carboxypenicillins) Examples •Administered by injection •Identical antibacterial spectrum to carbenicillin •Smaller doses required compared to carbenicillin •More effective against P. aeruginosa •Fewer side effects •Can be administered with clavulanic acid TICARCILLINTICARCILLIN S N Me Me O HH CO2H H N O CO2H S Examples of broad spectrum penicillinsExamples of broad spectrum penicillins
  • 49. Problem 3 - Range of ActivityProblem 3 - Range of Activity Class 3 - Urea group at the α-position (ureidopenicillins) Examples •Administered by injection •Generally more active than carboxypenicillins vs. streptococci and Haemophilus species •Generally have similar activity vs Gram -ve aerobic rods •Generally more active vs other Gram -ve bacteria •Azlocillin is effective vs P. aeruginosa •Piperacillin can be administered alongside tazobactam Azlocillin Mezlocillin Piperacillin S N Me Me O HH CO2H H N O NH O R2N HN N O N N O MeO2S N N OO Et Examples of broad spectrum penicillinsExamples of broad spectrum penicillins
  • 50. SAR of cephalosporins 1. 7-Acylamino substituents: a) Acylation of amino group generally increases the potency against gram-positive bacteria, but it is accompanied by a decrease in gram-negative potency. b) High antibacterial activity is observed only when the new acyl groups are derived from carboxylic acids for gram-positive bacteria. c) Substituents on the aromatic ring that increases lipophilicity provide higher gram-positive activity and generally lower gram-negative activity. d) The phenyl ring in the side-chain can be replaced with other heterocycles with improved spectrum of activity and pharmacokinetic properties, and these include thiophene, tetrazole, furan, pyridine, and aminothiazoles 2. C-3 substituents:The nature of C-3 substituents influences pharmacokinetic and pharmacological properties as well as antibacterial activity. Modification at C-3 position has been made to reduce the degradation (lactone of desacetyl cephalosporin) of cephalosporins.
  • 51. SAR of cephalosporins 3. Pyridine and imidazole-replaced acetoxy groups show improved activity againstP.aeruginosa.Displacement of acetoxy group by azide ion yields derivatives with relatively low gram-negative activity. 4. Displacement with aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram-negative bacteria with improved pharmacokinetic properties. 5. Replacement of acetoxy group at C-3 position with —CH3, Cl has resulted in orally active compounds. 6. Oxidation of ring sulphur to sulphoxide or sulphone greatly diminishes or destroys the antibacterial activity. 7. Replacement of sulphur with oxygen leads to oxacepam (latamoxef) with increased antibacterial activity, because of its enhanced acylating power. 8. Similarly, replacement of sulphur with methylene group (loracarbef) has greater chemical stability and a longer half-life. 9. The carboxyl group of position-4 has been converted into ester prodrugs to increase bioavailability of cephalosporins, and these can be given orally as well. Examples include cefuroxime axetil and cefodoxime proxetil 10. Olefinic linkage at C 3-4 is essential for antibacterial activity. Isomerization of the double bond to 2-3 position leads to great losses in antibacterial activity.
  • 53. Introduction  Antibiotics contain an aminocyclitol moiety to which aminosugars are glycosidically linked.  They may be more correctly called aminocyclitol antibiotics. O O O O H2C NH2 H2N OH NH2 HO NH2 HO NH2 Tobramycin HOH2C HO 1 1'' 2''3''4'' 5'' 1' 5' 4' 3' 2' 3 4 5 6 6' 2 6'' O O O O R1H2C HO HO R2 H2N OH NH2 HOH2C HO NH2 HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Kanamycins 53REVOLUTIOPHARMD.CO M
  • 54. Aminocyclitols???  Cyclohexanes with several substituted or unsubstituted amino and hydroxyl groups which bring them high water solubility.  Streptidine and Streptamine can be called 1,3-diguanidino and 1,3-diamino inositol, respectively. NH2 OH HO H2N NH2 OH HO H2N OH H2N HO HO HO HO OH NHCH3 H3CO 1 2 3 45 6 1 2 3 4 56 1 2 345 6 H N OH HO HN HO OH1 2 3 45 6 NH NH2 NH H2N Streptamine Streptidine 2-Deoxystreptamine NHCH3 OH HO 1 2 3 4 56 OH Spectinamine Fortamine 54REVOLUTIOPHARMD.CO M
  • 55.  All have an aminohexose as the amino sugar and some have a pentose as an extra sugar. O O O O O O OH CH2OH H2N NH2 HO NH2 HO HO OH HO HO R1 R2 NH2 Paromomycin I: R1= H; R2= CH2NH2 Paromomycin II: R1= CH2NH2; R2= H 1 2 3 34 5 6 1' 2' 3' 4' 5' 6' 12 3 44 5 1 2 55REVOLUTIOPHARMD.CO M
  • 56. Spectrum of Antimicrobial Activity  Aminoglycosides are broad-spectrum antibiotics effective in: 1. Systemic Infections caused by aerobic G(-) bacillus (klebsiella, proteus, enterobacters). 2. Tuberculosis, Brucellusis, Tularaemia and yersinia infections. 3. Amoebic dysentery, shigellosis and salmonellosis. 4. Pneumonia and urinary infections caused by Pseudomona aeroginosa.  G(+) and G(-) aerobic cocci except staphylococci and anaerobic bacteria are less susceptible. 56REVOLUTIOPHARMD.COM
  • 57. Microbial Resistance against Aminoglycosides  Resistant strains have emerged against streptomycin, kanamycin and gentamycin in clinic.  R factor is resposible for the production of aminoglycoside deactivating enzymes: 1) Acetyl transferases (AAC) 2) Phosphotransferases (APH), 3) Nucleotidyl transferases (ANT)  These enzymes transfer to hydroxyl and amino groups of the drug. 57REVOLUTIOPHARMD.CO M
  • 58. Aminoglycoside Deactivating Enzymes • AAC acetylates 3-NH2of the ring II, and 2`, 6`- NH2 of the ring I. • APH phosphorylates 3`-OHof the ring I and 2``-OH of the ring III. • ANT adenylates 2``,4``-OH of the ring III and 4`-OH of the ring I. O O O O OH NH2 OH H2N OH NH2 H2N HO H2N HO OH 1 2 3 45 6 1' 2' 4' 1'' 3' 2'' 5' 3'' 5'' 4'' 6'' 6' I II III ANT-4' ANT-4'' ANT-2'' , APH-2'' AAC- 6' AAC- 2' APH- 3' AAC- 3 Kanamycin B 58REVOLUTIOPHARMD.CO M
  • 59. Gentamycin and Deactivating Enzymes O O O O HC NH2 H2N OH NH H3C NH2 HO 1'' 2''3''4'' 5'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Garosamine 2-Deoxystreptamine Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H OH CH3 NHR2R1 Lack 3`-OH APH Resistant Axial and tertiary 4``-OH instead of equatorial secondary 4``-OH in Kanamycin ANT Resistant Secondary amino group at 6`-NH2 in Gentamycin C1, spacial hynderance AAC Resisistant I II III 59REVOLUTIOPHARMD.CO M
  • 60. Kanamycin and Deactivatig Enzymes O O O O R1H2C HO HO R2 H2N OH NH2 HOH2C HO NH2 HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Kanosamine 2-Deoxystreptamine Kanamycin A: R1= NH2 ; R2 = OH Kanamycin B: R1 = NH2 ; R2 = NH2 Kanamycin C: R1= OH; R2 = NH2 III II I 3`-deoxy derivative APH Resistant 4`-deoxy derivative ANT Resistant 60REVOLUTIOPHARMD.CO M
  • 61. Amikacin and Dactivating Enzymes • 1-N-L-(-)-amino-α-hydroxybutyric acid derivative of kanamycin A. Susceptible only against the action of AAC 6`-amino and ANT 4`-OH, resistant against all other deactivating enzymes. O O O O H2NH2C HO HO OH H2N OH NH2 HOH2C HO NH HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Amikacin, L-AHBA derivative of Kanamycin A C C O CH2 CH2 NH2 OH H 2 2-Deoxystreptamine Kanosamine 61
  • 62. Tobramycin and Deactivating Enzymes O O O O H2C NH2 H2N OH NH2 HO NH2 HO NH2 2-Deoxystreptamine Tobramycin HOH2C HO 1 1'' 2''3''4'' 5'' 1' 5' 4' 3' 2' 3 4 5 6 6' 2 6'' Lack 3`-OH APH Resistant 62REVOLUTIOPHARMD.CO M
  • 63. The Minor Mechanism for Microbial Resistance Decreased uptake of the drug in some strains of p. aeroginosa in hospital infections because of blockade in the active transport of aminoglycosides. Aminoglycoside molecules attach through their cationic groups to anionic portions of membrane phospholipids of bacteria. Upon this attachment the the ATP-dependent uptake occurs. Bivalent cations such as Ca2+ and Mg2+ compete with the drug in this process and antagonise them. Anaerobic bacteria lack the ATP-dependent uptake process, so they are resistant to aminoglycosides.63REVOLUTIOPHARMD.COM
  • 64. SAR of Aminoglycosides O O O O OH NH2 OH H2N OH NH2 H2N HO H2N HO OH 1 2 3 45 6 1' 2' 4' 1'' 3' 2'' 5' 3'' 5'' 4'' 6'' 6' I II III ANT-4' ANT-4'' ANT-2'' , APH-2'' AAC- 6' AAC- 2' APH- 3' AAC- 3 Kanamycin B  Ring I is very necessary for broad-spectrum antibacterial activity.  2` and 6`-NH2 groups are specially important. Exchanging of one of them in kanamycin B with hydroxyl group decreases the activity (kanamycin A, C) 64REVOLUTIOPHARMD.CO M
  • 65. SAR of ring I continued Methylation of C-6` or 6`- NH2 doesn’t alter the antibacterial activity, but increases the resistance against AAC. O O O O HC NH2 H2N OH NH H3C NH2 HO 1'' 2''3''4'' 5'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Garosamine 2-Deoxystreptamine Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H OH CH3 NHR2R1 Lack 3`-OH APH Resistant Axial and tertiary 4``-OH instead of equatorial secondary 4``-OH in Kanamycin ANT Resistant Secondary amino group at 6`-NH2 in Gentamycin C1, spacial hynderance AAC Resisistant I II III 65REVOLUTIOPHARMD.CO M
  • 66. SAR of ring I continued Omitting the 3`-OH and/or 4`-OH in kanamycin doesn’t decrease the antibacterial activity but increases the resistance against AAC: 3`,4`- dideoxykanamycin B: Dibekacin. The same is true for gentamicin. O O O O R1H2C HO HO R2 H2N OH NH2 HOH2C HO NH2 HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Kanosamine 2-Deoxystreptamine Kanamycin A: R1= NH2 ; R2 = OH Kanamycin B: R1 = NH2 ; R2 = NH2 Kanamycin C: R1= OH; R2 = NH2 III II I 3`-deoxy derivative APH Resistant 4`-deoxy derivative ANT Resistant 66REVOLUTIOPHARMD.CO M
  • 67. SAR of ring I continued O OH H3C NHCH3 OH O NHR HO O O NH2 CH2OH H2N 16 2 4 3 5 1' 2' 3' 4' 1'' 2''3'' 5'' 4'' 5' Sisomicin: R=H Netilmicin: R=C2H5 Omitting the 3`-OH and 4`-OH and the addition of a double bond between C-4` and C-5`has the same effect. 67REVOLUTIOPHARMD.CO M
  • 68. SAR of Aminoglycosides continued O O O O H2NH2C HO HO OH H2N OH NH2 HOH2C HO NH HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Amikacin, L-AHBA derivative of Kanamycin A C C O CH2 CH2 NH2 OH H 2 2-Deoxystreptamine Kanosamine Ring II is flexible toward changes. 1-NH2 in kanamycin can be acylated and the antibacterial activity remains almost unchanged , but resistance against deactivating enzymes increases: Amikacin 68REVOLUTIOPHARMD.CO M
  • 69. SAR of ring II continued 1-NH2ethylation of sisomycin saves the antibacterial activity and increases the enzymatic resistance: Netilmycin O OH H3C NHCH3 OH O NHR HO O O NH2 CH2OH H2N 16 2 4 3 5 1' 2' 3' 4' 1'' 2''3'' 5'' 4'' 5' Sisomicin: R=H Netilmicin: R=C2H5 69REVOLUTIOPHARMD.CO M
  • 70. SAR of Aminoglycosides continued O O O O HC NH2 H2N OH NH H3C NH2 HO 1'' 2''3''4'' 5'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Garosamine 2-Deoxystreptamine Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H OH CH3 NHR2R1 I II III  Ring III functional groups are less sensitive to modifications:  2``-deoxy gentamicins are less active than 2``-OH ones, but 2``-NH2 derivative (seldomycin) are very active.  3``- NH2 can be primary or secondary.  4``-OH can be axial or equatorial, the former is resistant against the deactivating enzymes (ANT). 70REVOLUTIOPHARMD.CO M
  • 71. Mechanism of Action of Aminoglycosides Inhibition of protein biosynthesis initiation upon attachment to 30s portion of ribosomes. Misreading mutation of the genetic code and the synthesis of nonesense proteins which are not normal proteins so they cannot take part in cellular activities. Nonesense proteins disturb the semipermeability of the bacterial cell and aminoglycoside molecules enter the cell easily and kill it. 71REVOLUTIOPHARMD.COM
  • 72. Therapeutic Agents Kanamycin O O O O R1H2C HO HO R2 H2N OH NH2 HOH2C HO NH2 HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Kanosamine 2-Deoxystreptamine Kanamycin A: R1= NH2 ; R2 = OH Kanamycin B: R1 = NH2 ; R2 = NH2 Kanamycin C: R1= OH; R2 = NH2 III II I  Isolated from cultures of Streptomyces kanamyceticus. The least toxic member in the market is kanamycin A.  It is used for the treatment of GI infections, such as dysentery and systemic G(-) bacillus infections caused by klebsiella, proteus, enterobacters.  For disinfection of GI before an operation. 72REVOLUTIOPHARMD.CO M
  • 73. Amikacin O O O O H2NH2C HO HO OH H2N OH NH2 HOH2C HO NH HO 1'' 2''3''4'' 5''6'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Amikacin C C O CH2 CH2 NH2 OH H 2 2-Deoxystreptamine Kanosamine A semisynthetic derivative of kanamycin A. It is used in the treatment of infections caused by Mycobacterium tuberculosis, Yersinia tularensis, Pseudomona aeroginosa. The suffix “micin” denotes its origin. 73REVOLUTIOPHARMD.CO M
  • 74. Tobramycin • Isolated from cultures of Streptomyces tenebrarius. • Antimicrobial activity against resistance P.aeroginosa. O O O O H2C NH2 H2N OH NH2 HO NH2 HO 2-Deoxystreptamine Tobramycin HOH2C HO 1 1'' 2''3''4'' 5'' 1' 5' 4' 3' 2' 3 4 5 6 2 6'' Lacks 3`-OH APH Resistant 74REVOLUTIOPHARMD.CO M
  • 75. Gentamicin  Isolated from cultures of Micromonospora purpurea.  The suffix “micin” denotes its origin.  It is used against urinary infections caused by G(-) and pseudomona. O O O O HC NH2 H2N OH NH H3C NH2 HO 1'' 2''3''4'' 5'' 1' 2' 3' 4' 6' 5' 1 23 4 5 6 Garosamine 2-Deoxystreptamine Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H OH CH3 NHR2R1 Lacks 3`-OH APH Resistant Axial and tertiary 4``-OH instead of equatorial secondary 4``-OH in Kanamycin ANT Resistant Secondary amino group at 6`-NH2 in Gentamycin C1, spacial hynderance AAC Resisistant I II III 75REVOLUTIOPHARMD.CO M
  • 76. Neomycin O O O O O O OH CH2OH H2N NH2 HO NH2 HO HO NH2 HO HO H2NH2C R2 NH2 2-Deoxystreptamine Neosamine C Neosamine C 1 2 3 34 5 6 1' 2' 3' 4' 5' 6' 12 3 44 5 1 2 D-Ribose Neomycin Isolated from cultures of Streptomyces fradia along with an antifungal subsance: Fradicin. Effective against GI and dermal infections. 76REVOLUTIOPHARMD.CO M
  • 77. Netilmicin O OH H3C NHCH3 OH O NHR HO O O NH2 CH2OH H2N 16 2 4 3 5 1' 2' 3' 4' 1'' 2''3'' 5'' 4'' 5' Sisomicin: R=H Netilmicin: R=C2H5  A semisynthetic ethyl derivative of sisomicin isolated from Micromonospora inyoensis.  Ethylation causes spacial hynderance against APH and ATN enzymes.  Against gentamicin resistant pseudomona and proteus. 77REVOLUTIOPHARMD.CO M
  • 78. Streptomycin O O H N HO OH OH NH NH H2N OHO H3C CHO O NHCH3 OH HO HO H2N HN Streptidine L-Streptose N- Methyl-L-Glucosamine Streptomycin 1'' 2'3' 4' 12 3 4 1' 2''3'' 4'' 5'' 6 5  Has a different aminocyclito (a 1,3-diguanidinoinositol). 78REVOLUTIOPHARMD.CO M
  • 79. Streptomycin continued Isolated from cultures of Streptomyces griseus. It was introduced against tuberculosis in 1943, kanamycin and amikacin are effective against tuberculosis, but not as much as streptomycin. Streptomycin brought Waxman the Noble prize in 1952. 79REVOLUTIOPHARMD.COM
  • 80. Mechanism of Chemical incompatility of Aminoglycosides with β-lactams Acylation of aminocyclitol portion by the β-lactam molecule. Begins with nucleophilic addition of the amino group to the carbonyl group of β-lactam ring. N O NHCOR HOOC O NHCOR HN HO O O SUGAR NH2 N SUGAR HOOC H2N HO O O SUGAR NH2 SUGAR 80REVOLUTIOPHARMD.CO M
  • 81. Tetracyclines • The tetracyclines are primarily bacteriostatic; inhibit protein synthesis by binding to 305 ribosomes in susceptible organism. • Subsequent to such binding, attachment of aminoacyl-t-RNA to the mRNA-ribosome complex is interferred. • As a result,the peptide chain fails to grow.
  • 84. SAR of tetracyclin 1. C-1 substituents: The keto-enol system of the A-ring is indispensable for antibacterial activity. No variation at the C-1 position has been successful. 2. C-2 substituents: The carboxamide moiety is present in all naturally occurring tetracyclines and this group is crucial for antibacterial activity. The amide is best left unsubstituted, or mono-substitution is acceptable in the form of activated 3. C-3 substituents: In conjugation with the C-1 position, the keto-enol conjugated system is imperative for antibacterial activity. 4. C-4 substituents: The naturally occurring tetracyclines contain α-C-4 dimethylamino substituent that favourably contributes to the keto-enolic character of the A-ring. Replacement of dimethylamino group with a hydrazone, oxime, or hydroxyl group leads to a pronounced loss of activity, probably due to the increase in heteroatom basicity. 5. C-4a substituents: The α-hydrogen at C-4a position of tetracyclines is necessary for useful antibacterial activity. 6. C-5 substituents: Many naturally occurring antibacterial tetracyclines have an unsubstituted methylene moiety at the C-5 position. However, oxytetracycline contains C-5 α-hydroxyl group and was found to be a potent compound, and has been modified chemically to some semi-synthetic tetracyclines. Alkylation of the C-5 hydroxyl group results in a loss of activity.
  • 85. Effect of pH on tetracyclines • An interesting property of tetracyclines is their ability to undergo epimerization at C-4 in solutions of intermediate pH range. These isomers are called epitetracyclines. Under the influence of the acidic conditions, an equilibrium is established in about one day consisting of approximately equal amount of isomers. Epitetracyclines exhibit much less activity than natural isomers. • Strong acids and bases attack the tetracyclines having a hydroxyl group on C-6, causing a loss in activity through modification of C-ring. • Strong acids produce dehydration through a reaction involving the C-6 hydroxyl group and C-5a hydrogen. • Bases promote a reaction between the C-6 hydroxyl group and the ketone group at the C-11 position, causing the bond between the C-11 and C-11a atoms to cleave and to form the lactone ring found in the inactive isotetracycline.
  • 86. SAR of tetracyclin 7. C-5a substituents: The configuration of the naturally occurring tetracyclines places the C-5a hydrogen atom in an α-configuration. Epimerization is detrimental to antibacterial activity. 8. C-6 substituents: The C-6 position is tolerant of a variety of substituents. The majority of tetracyclines have an α-methyl group and a β-hydroxyl group at this position. Demeclocyclin is a naturally occurring C-6 demethylated chlortetracycline with an excellent activity. This C-6 methyl group contributes little to the activity of tetracycline. Similarly, the C-6 hydroxyl group also appears to offer little in terms of antibacterial activity; removal of this group affords doxycycline, which is a superb antibacterial. 9. C-7 and C-9 substituents: The nature of the aromatic D-ring predisposes the C-7 position to electrophilic substitution, and nitro and halogen groups have been introduced. 10. The C-7 acetoxy, azido, and hydroxyl tetracyclines are inferior in terms of antibacterial activity. 11. C-10 substituents: The C-10 phenolic moiety is absolutely necessary for antibacterial activity. 12. C-11 substituents: The C-11 carbonyl moiety is part of one of the conjugated keto-enol systems required for antibacterial activity. 13. C-12a substituents: The C-12a hydroxyl group is needed for antibacterial activity, although this
  • 87. Chloramphenicol • MOA of Chloramphenicol-it inhibits bacterial protein synthesis by interferring with 'transfer' of the elongating peptide chain to the newly attached aminoacyl-tRNA at the ribosome-mRNA complex. • It specifically attaches to the 50S ribosome and thus may hinder the access of aminoacyl- tRNA to the acceptor site for amino acid incorporation • it prevents formation of peptide bonds
  • 88. Microlide antibiotics • MACROLIDE ANTIBIOTICS-The macrolide antibiotics have three common chemical characteristics: • A large lactone ring • A ketone group • A glycosidically linked amino sugar • These are antibiotics having a macrocyclic lactone ring with attached sugars. • Among the many antibiotics isolated from the actinomycetes is the group of chemically related compounds called the macrolides • Erythromycin is the first member discovered in the 1950s,Roxithromycin, Clarithromycin and Azithromycin.
  • 90. SAR of Microlide • A number of strategies have been utilized to improve the acid stability of erythromycin. • The first approach involved the addition of hydroxylamine to the ketone to form oxime— e.g., roxithromycin. • The second approach involves an alteration of C-6 hydroxyl group, which is the nucleophilic functionality that initiates erythromycin degradation. Modification that removes the nucleophilic nature of this hydroxyl group can retain antibacterial properties if the size of the group is kept small so as not to affect the ribosomal binding —e.g., clarithromycin. • The azalides (e.g., azithromycin) are semi-synthetic 15-membered congeners in which a nitrogen atom has been introduced to expand a 14-membered precursor, and this leads to an extended spectrum of action.