Transcript patrick_ch16_p2

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 16
ANTIBACTERIAL AGENTS
Part 2: Cephalosporins
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CEPHALOSPORINS
O
R
C
H
N
H
H
S
N
OAc
O
CO2H
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1. Introduction
•
Antibacterial agents which inhibit bacterial cell wall synthesis
•
Discovered from a fungal colony in Sardinian sewer water
(1948)
•
Cephalosporin C identified in 1961
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2. Structure of Cephalosporin C
7-Aminoadipic side chain
H H
N
H2N
H
CO2H
7
8
O
H
6
5
N
S
1
4
2
3
O
O
Dihydrothiazine
ring
b-Lactam
ring
H
H
Me
O
CO2H
H2N
C
S
N
O
O
CO2H
C
Me
O
7-Aminocephalosporinic acid (7-ACA)
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H H
N
H2N
3. Properties of Cephalosporin C
H
CO2H
7
8
O
H
6
5
N
S
1
4
2
3
O
CO2H
O
C
Me
O
Disadvantages
• Polar due to the side chain - difficult to isolate and purify
• Low potency - limited to the treatment of urinary tract
infections 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
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4. Biosynthesis of Cephalosporins
H2N
R
OH
O
H Cys
SH
HO
CO2H Me Val
Me
H2N
CO2H
C
O
Me
H H
N
R
O
H
S
N
O
O
CO2H
C
Me
O
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5. SAR of Cephalosporins
H H
N
R
7
8
O
H
6
S
1
5
4
N
2
3
O
CO2H
O
C
Me
O
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
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6. Mechanism of Action
H H
N
7
R
O
H
S
N
O
O
CO2H
•
C
O
Me
H
Enzyme
S
-CH3CO2-
O
N
O
O
Ser
OH
Ser
H H
N
R
CO2H
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
H2N
H
H
S
RCOCl
N
O
O
CO2H
H H
N
R
C
O
Me
O
H
S
N
O
O
CO2H
C
Me
O
7-ACA
•
•
•
7-ACA not available by fermentation
7-ACA not available by enzymatic hydrolysis of cephalosporin C
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 unreactive secondary amide in
the presence of a labile b-lactam ring
H
N
R1
H
H
S
PCl5
7
O
N
4
O
3
R1
N
H
R1
ROH
Cl
OAc
H
H2 O
OR
O
CO2SiMe3
N
-R1CO2H
O
Imino chloride
Imino ether
Protecting group
H2N
H
H
N
CO2H
7-ACA
H
H
S
R2COCl
OAc
O
H
N
R2
S
O
N
OAc
Range of cephalosporins
O
CO2H
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8. First Generation Cephalosporins
Cephalothin
H H
N
7
S
O
H
S
3
N
OAc
O
CO2H
•
•
•
•
•
•
•
•
•
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 S. 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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8. First Generation Cephalosporins
Cephalothin - drug metabolism
H H
N
7
S
O
H
H H
N
S
3
N
O
CO2H
OAc
S
Metabolism
O
H
S
N
OH
O
CO2H
Less active
OH is a poorer leaving group
Strategy
• Replace the acetoxy group with a metabolically stable leaving
group
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8. First Generation Cephalosporins
Cephaloridine
H H
N
7
S
O
H
S
3
N
N
O
CO2
•
The pyridine ring is stable to metabolism
•
The pyridine ring is a good leaving group (neutralisation of
charge)
•
Exists as a zwitterion and is soluble in water
•
Poorly absorbed through the gut wall
•
Administered by injection
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8. First Generation Cephalosporins
Cefalexin
H2N
H
H H
N
7
O
H
S
3
N
Me
O
CO2H
•
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
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8. First Generation Cephalosporins
Synthesis of cephalosporins with a 3-methyl substituent
R
C
H
N
O
H
6
N
O
OH
O
S
2
H2 O2
Me
Me
S
N
CO2Me
S
N
Me
H
OH
CH3
CO2Me
OH
H
S
CH2
N
Me
H
- H
N
H
H
S
H
OH
CH3
CO2Me
CH3
CO2Me
CO2Me
CO2Me
S
N
Me
Toluene/
PTSA
H
N
S
3
CH3
CO2Me
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8. First Generation Cephalosporins
Summary
•
•
•
•
•
•
•
•
Generally lower activity than comparable penicillins
Better range of activity than comparable penicillins
Best activity is against Gram-positive cocci
Useful against some Gram negative infections
Useful against S. 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 b-lactamases)
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9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H
N
HO2C
H2N
H
O
S
N
O
O
CO2H
C
NH2
Cephamycin C
O
•
Isolated from a culture of Streptomyces clavuligerus
•
First b-lactam to be isolated from a bacterial source
•
Modifications carried out on the 7-acylamino side chain
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9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H
N
7
S
O
S
3
N
O
CO2H
•
•
•
•
•
Cefoxitin
O
C
NH2
O
Broader spectrum of activity than most first generation
cephalosporins
Greater resistance to b-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.
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9. Second Generation Cephalosporins
9.2 Oximinocephalosporins
Me
O
N
C
O
H H
N
O
H
N
O
O
CO2H
•
•
•
•
•
•
Cefuroxime
S
C
NH2
O
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 P. aeruginosa
Used clinically against respiratory infections
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10. Third Generation Cephalosporins
Oximinocephalosporins
R
Me
Aminothiazole
ring
O
N
H2N
S
N
C
H H
N
H
S
CH2S
N
N
O
Cefotaxime
Ceftizoxime
CH2OCOMe
H
Me
N
R
O
N
Ceftriaxone
OH
O
CO2H
•
•
•
•
•
•
•
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. P. aeruginosa
Lack activity vs MRSA
Generally reserved for troublesome infections
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10. Third Generation Cephalosporins
Oximinocephalosporins
Me
Me
O
N
C
S
N
H2N
CO2H
H H
N
O
H
Ceftazidime
S
N
N
O
CO2
•
•
•
•
Injectable cephalosporin
Excellent activity vs. P. aeruginosa and other Gram -ve
bacteria
Can cross the blood brain barrier
Used to treat meningitis
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11. Fourth Generation Cephalosporins
Oximinocephalosporins
Me
O
N
H2N
S
R
N
C
H H
N
O
H
Me
S
N
CO2H
•
•
•
•
N
R
O
•
•
CH2
CH2 N
Cefipime
Cefpirome
Zwitterionic compounds
Enhanced ability to cross the outer membrane of Gram
negative bacteria
Good affinity for the transpeptidase enzyme
Low affinity for some b-lactamases
Active vs. Gram +ve cocci and a broad array of Gram -ve
bacteria
Active vs. P. aeruginosa
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