ANTIBACTERIAL AGENTS - Cephalosporins - SAR (Structure Activity Relationship )
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Transcript of ANTIBACTERIAL AGENTS - Cephalosporins - SAR (Structure Activity Relationship )
1 ©
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 16
ANTIBACTERIAL AGENTS
Part 2: Cephalosporins
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CEPHALOSPORINS
N
S
OAc
CO2H
O
HN H HC
O
R
N
S Me
Me
HN
CO2H
O
C H H
O
R
Penicillins Cephalosporins
Dihydrothiazine ring (system) Thiazolidine ring (system)
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1. Introduction
1. Antibacterial agents which inhibit bacterial
cell wall synthesis.
2. Discovered from a fungal colony in
Sardinian sewer water (1948).
3. Cephalosporin C identified in 1961.
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N
O
HHHN
O
S
CO2H
OC
Me
O
H2N
CO2H
7H
61
2
34
58
7-Aminoadipic side chain
2. Structure of Cephalosporin C
b-Lactam
ring
Dihydrothiazine
ring
N
O
HHH2N S
CO2H
OC
Me
O
7-Aminocephalosporinic acid (7-ACA)
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3. Properties of Cephalosporin C
Disadvantages
• Polar due to the side chain - difficult to isolate and purify
• Low potency (1/1000 the activity of Pen G)- limited to the treatment
of urinary tract infections (UTI) where it is concentrated in the
urine
• Not absorbed orally
Advantages
• Non toxic
• Lower risk of allergic reactions compared to penicillins
• More stable to acid conditions
• More stable to b-lactamases
• Ratio of activity vs. Gram -ve and Gram +ve bacteria is better
Conclusion
• Useful as a lead compound
N
O
HHHN
O
S
CO2H
OC
Me
O
H2N
CO2H
7H
61
2
34
58
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4. Biosynthesis of Cephalosporins
SH
H2N
CO2H
H
CO2H
H2NCys
ValMe
Me
R OH
O
HOC
Me
ON
O
HHHNR
O
S
CO2H
OC
Me
O
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5. SAR of Cephalosporins
Similar to penicillins • The b-lactam ring is crucial to the mechanism
• The carboxylic acid at position 4 is important to binding
• The bicyclic system is important in increasing ring strain
• Stereochemistry is important
• The acetoxy substituent is important to the mechanism
Possible modifications
• 7-Acylamino side chain
• 3-Acetoxymethyl side chain
• Substitution at C-7
N
O
HHHNR
O
S
CO2H
OC
Me
O
7 61
2
34
58
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SAR of Sephalosporins
Possible Modification Sites
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6. Mechanism of Action
N
O
HHHNR
O
S
CO2H
OC
Me
O
7
OH
Ser Enzyme
-CH3CO2-
N
O
HHHNR
O
S
CO2HO
Ser
Enzyme
• The Acetoxy group acts as a good leaving
group and aids the mechanism
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7. Variation of the 7-Acylamino Side Chain
Not possible to generate analogues by fermentation
Not possible to generate analogues by a full synthesis
Restricted to semi-synthetic procedure
• 7-ACA not available by fermentation.
• 7-ACA not available by enzymatic hydrolysis of cephalosporin C.
N
O
HHH2N S
CO2H
OC
Me
O
7-ACA
RCOCl N
O
HHHNR
O
S
CO2H
OC
Me
O
• Generated by a chemical hydrolysis
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7. Variation of the 7-Acylamino Side Chain
Generation of 7-ACA
• Need to hydrolyse a relatively un-reactive secondary amide in
the presence of a labile b-lactam ring
N
S
OAc
CO2SiMe3
O
H HHNR1
O3
7
4
Protecting group
PCl5
Imino chloride
O
HNR1
Cl
ROH
Imino ether
O
HNR1
OR
H2O
-R1CO2H
7-ACA
N
S
OAc
CO2H
O
H HH2N
R2COCl
N
S
OAc
CO2H
O
H HHNR2
O
Range of Cephalosporins
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8. First Generation Cephalosporins
Cephalothin N
O
HHHN S
CO2H
OAcOS
7
3
• First generation cephalosporin
• More active than penicillin G vs. some Gram -ve bacteria
• Less likely to cause allergic reactions
• Useful vs. penicillinase producing strains of Staphylococcus aureus
• Not active vs. Pseudonomas aeruginosa
• Poorly absorbed from GIT
• Administered by injection
• Metabolised to give a free 3-hydroxymethyl group
(deacetylation)
• Metabolite is less active
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Cephalothin - drug metabolism
Strategy
• Replace the acetoxy group with a metabolically stable leaving
group
N
O
HHHN S
CO2H
OAcOS
7
3
Metabolism N
O
HHHN S
CO2H
OHOS
Less active
OH is a poorer leaving group
8. First Generation Cephalosporins
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Cephaloridine
• The pyridine ring is stable to metabolism
• The pyridine ring is a good leaving group
(Neutralization of charge)
• Exists as a zwitterion and is soluble in water
• Poorly absorbed through the gut wall
• Administered by injection
N
O
HHHN S
CO2
NOS
7
3
8. First Generation Cephalosporins
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Cefalexin
• The methyl group at position 3 is not a good leaving group
• The methyl group is bad for activity but aids oral absorption -
mechanism unknown
• Cefalexin can be administered orally
• A hydrophilic amino group at the a-carbon of the side chain
helps to compensate for the loss of activity due to the methyl
group
N
O
HHHN S
CO2H
Me
O
H2N H
7
3
8. First Generation Cephalosporins
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Synthesis of Cephalosporins with a 3-methyl substituent
8. First Generation Cephalosporins
O
N
HNC
S Me
Me
CO2Me
H
R
O6 2
Toluene/
PTSA S
OH
N
CH2
Me
CO2Me
H
N
CO2Me
S
OH
CH3
CH3
N
S
CO2Me
- HS
N
HCO2Me
OH
CH3
H
CH3
N
S
CO2Me
H
3
CO2Me
Me
MeS
N
O
H2O2
H
H
OH H
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1st Generation Cephalosporins
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Summary
8. First Generation Cephalosporins
• Generally lower activity than comparable penicillins
• Better range of activity comparable penicillins
• Best activity is against Gram-positive cocci
• Useful against some Gram negative infections
• Useful against Staphylococcus aureus and
streptococcal infections when penicillins have to be
avoided
• Poorly absorbed across the gut wall (except for 3-
methyl substituted Cephalosporins)
• Most are administered by injection
• Resistance has appeared amongst Gram negative
bacteria (presence of more effective β-lactamases)
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9.1 Cephamycins
9. Second Generation Cephalosporins
• Isolated from a culture of Streptomyces clavuligerus
• First β-lactam to be isolated from a bacterial source
• Modifications carried out on the 7-acylamino side chain
N
O
HOMeHN S
CO2H
OO
CNH2
O
HO2C
H2N H
Cephamycin C
The parent
compound
Methoxy Group at C7
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Cefoxitin
• Broader spectrum of activity than most first generation
cephalosporins.
• Greater resistance to β-lactamase enzymes.
• The 7-methoxy group may act as a steric shield.
• The urethane group is stable to metabolism compared to
the ester.
• Introducing a methoxy group to the equivalent position
of penicillins (position 6) eliminates activity.
N
O
HOMeHN S
CO2H
OO
CNH2
O
S
7
3
9.1 Cephamycins
9. Second Generation Cephalosporins
Cephalothin
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Cefuroxime
• Much greater stability against some b-lactamases
• Resistant to esterases due to the urethane group
• Wide spectrum of activity
• Useful against organisms that have gained resistance to penicillin
• Not active against Pseudomonas aeruginosa
• Used clinically against respiratory infections
9. Second Generation Cephalosporins
N
O
HHHN S
CO2H
O
C
O
CNH2
O
O
NO
Me
9.2 Oximinocephalosporins
Zinnat
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Second Generation
Cephalosporins
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• Aminothiazole ring enhances penetration of cephalosporins across the
outer membrane of Gram -ve bacteria
• May also increase affinity for the transpeptidase enzyme
• Good activity against Gram -ve bacteria
• Variable activity against Gram +ve cocci
• Variable activity vs. Pseudomonas aeruginosa
• Lack activity vs. Methicillin-resistant Staphylococcus aureus (MRSA) +ve
• Generally reserved for troublesome infections
Oximinocephalosporins
N
O
HHHN S
CO2H
R
C
O
N
S
NO
Me
H2N
CH2OCOMeH
CefotaximeCeftizoxime
N
NNCH2S
O
OH
Me
Ceftriaxone
R
Aminothiazole
ring
10. Third Generation Cephalosporins
Sodium(6R,7R)-3-[(acetyloxy)methyl]-7-[[(Z)-2-(2-aminothiazol-4-yl)-2- (methoxyimino)acetyl]amino]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
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• Injectable cephalosporin
• Excellent activity vs. Pseudomonas aeruginosa and other
Gram -ve bacteria
• Can cross the blood brain barrier
• Used to treat meningitis
10. Third Generation Cephalosporins
N
O
HHHN S
CO2
N
C
O
S
N
NO
H2N
Me CO2HMe
Ceftazidime
Oximinocephalosporins
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-
oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
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• Zwitterionic compounds
• Enhanced ability to cross the outer membrane of Gram
negative bacteria
• Good affinity for the transpeptidase enzyme
• Low affinity for some β-lactamases
• Active vs. Gram +ve cocci and a broad array of Gram -ve
bacteria
• Active vs. Pseudomonas aeruginosa
11. Fourth Generation Cephalosporins
Oximinocephalosporins
N
O
HHHN S
CO2H
R
C
O
N
S
NO
Me
H2N
NCH2
Me
Cefipime
CefpiromeNCH2
R
(Cefrom)
1-methylpyrrolidinium-1-yl
5H,6H,7H-cyclopenta[b]pyridin-1-ium
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Cefquinome
tetrahydroquinolinium
derivative
-Resistant to β-lactamase.
-Its zwitterionic rapid penetration across biological membranes,
including porins.
-Has a higher affinity to target penicillin binding proteins.
-Besides zwitterionic, it is also made of β-lactam nucleus, quaternary
ammonium, and aminothiazolyl moiety
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Imidazo-pyridazin
derivative
Cefozopran
5-amino-1,2,4-
thiadiazol-3-ylidene
(-)-1-[[(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)glyoxylamido]-2-
carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1H-
imidazo[1,2-b]pyridazin-4-ium hydroxide inner salt, 7²-(Z)-(O-
methyloxime)
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5th generation:
Ceftobiprole (Zeftera/Zevtera)
• Injectable
• Activity against methicillin-resistant Staphylococcus aureus (mrsu), penicillin-resistant Streptococcus pneumoniae (prsp), Pseudomonas aeruginosa, and Enterococci.
• It was discovered by Basilea Pharmaceutical and was developed by Johnson & Johnson Pharmaceutical Research and Development.
• It has been shown to be statistically non-inferior to the combination of vancomycin and ceftazidime for the treatment of skin and soft tissue infections.
• Ceftobiprole has been granted "fast-track" status from the FDA and is licensed for complicated skin infections.
pyrrolidinyl-3-
pyrrolidinylidene
methyl
5-amino-1,2,4-
thiadiazol-3-ylidene
Hydroxylimine
broad-
spectrum
activity
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Ceftobiprole (Zeftera/Zevtera)
5-Amino-1,2,4-
thiadiazol-3-ylidene Pyrrolidinyl-3-
pyrrolidinylidene methyl
Hydroxylimine
First of a new class of parenteral cephem antibiotics
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Ceftobiprole medocaril
http://www.slideshare.net/banuman35/cephalosporins-history
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5th generation
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Structure–activity relationships for Ceftaroline (adapted
from Zhanel et al.,15 with permission).
Laudano J B J. Antimicrob. Chemother. 2011;66:iii11-iii18
© The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
All rights reserved. For Permissions, please e-mail: [email protected]
1 ©
Chemical structures for ceftaroline fosamil
(prodrug) and ceftaroline (active metabolite).
Biek D et al. J. Antimicrob. Chemother. 2010;65:iv9-iv16
© The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial
Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 ©
Ceftolozane (5th generation)
Ceftolozane
Approved January 2015
Intravenous
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Summary Cephalosporins contain a strained β-lactam ring fused to a
dihydrothiazine ring.
In general, first-generation cephalosporins offer advantages over
penicillins in that they have greater stability to acid conditions and
β-lactamases, and have a good ratio of activity against Gram-
positive and Gram-negative bacteria. However, they have poor
oral availability and are generally lower in activity.
Variation of the 7-acylamino side chain alters antimicrobial
activity, whereas variation of the side chain at position 3
predominantly alters the metabolic and pharmacokinetic
properties of the compound. Introduction of a methoxy
substitution at C-7 is possible.
Semisynthetic cephalosporins can be prepared from 7-
aminocephalosporanic acid (7-ACA).
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7-ACA is obtained from the chemical hydrolysis of cephalosporins.
This requires prior activation of the side chain to make it more
reactive than the β-lactam ring.
Deacetylation of cephalosporins occurs metabolically to produce
inactive metabolites. Metabolism can be blocked by replacing the
susceptible acetoxy group with metabolically stable groups.
A methyl substituent at position 3 is good for oral absorption but bad
for activity unless a hydrophilic group is present at the α-position of
the acyl side chain.
3-Methylated cephalosporins can be synthesized from penicillins.
Cephamycins are cephalosporins containing a methoxy group at
position 7.
Oximinocephalosporins have resulted in several generations of
cephalosporins with increased potency and a broader spectrum of
activity, particularly against Gram-negative bacteria.