Medicinal Chemistry
Lectures Note 7:
Cephalosporins
1. Introduction
•Antibacterial agents which inhibit bacterial cell wall synthesis
•Discovered from a fungal colony in Sardinian sewer water which
periodically cleared microorganisms (1948)
•Cephalosporin C identified by X-ray in 1961 in Oxford University
2. Structure of Cephalosporin C
7-Aminoadipic side chain
H H H
H2N N S
1
7 6 2
H
CO2H O 8 5 3
N 4 O Me
O C
CO2H O
-Lactam Dihydrothiazine
ring ring
H H
H2N S
N O Me
O C
CO2H O
7-Aminocephalosporinic acid (7-ACA)
H H H
H2N N S
1
3. Properties of Cephalosporin C H
CO2H O
7
8
6
5
N 4
2
3
O Me
O C
CO2H O
Disadvantages
•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 -lactamases
•Ratio of activity vs Gram -ve and Gram +ve bacteria is better
Conclusion
•Useful as a lead compound
4. Biosynthesis of Cephalosporins
H Cys SH
H2N HO Me H H H
R N S
C
R OH CO2H Me Val O O
Me
N O Me
H2N O C
O
CO2H O
CO2H
5. SAR of Cephalosporins
H H H
R N S
1
7 6 2
O 8 5 3
N 4 O Me
O C
CO2H O
•Similar to penicillins
•The -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
6. Mechanism of Action
H H H
S
R N H H H
R N S
7
O -CH3CO2-
N O Me O
O C N
O
CO2H O
O
CO2H
OH Ser
Ser Enzyme
Enzyme
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
H H H H H
S R N S
H2N
RCOCl O
N O Me N O Me
C O C
O
O CO2H O
CO2H
7-ACA
A problem here!!
7. Variation of the 7-Acylamino Side Chain
Generation of 7-ACA
H H H H H
R1 N S R1 N ROH R1 N H2O
PCl5
7
O N OAc Cl OR -R1CO2H
3
O 4 O O
CO2SiMe3 Imino chloride Imino ether
Protecting group
H H H H H
H 2N S R2 N S
R2COCl
Range of cephalosporins
N OAc O N OAc
O O
CO2H CO2H
7-ACA
8. First Generation Cephalosporins
Cephalothin
H H H
S
N
7
S O 3
N OAc
O
CO2H
•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
8. First Generation Cephalosporins
Cephalothin - drug metabolism
H H H
S
H H H
S
N N
7
S O 3 S O
N OAc N OH
O Metabolism O
CO2H CO2H
Strategy
Replace the acetoxy group with a metabolically stable leaving group
8. First Generation Cephalosporins
Cephaloridine
H H H
S
N
7
S O 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
8. First Generation Cephalosporins
Cefalexin
H2N H
H H H
S
N
7
O 3
N
O Me
CO2H
•The 3-methyl group is a poor leaving group
•Methyl group is bad for activity but aids oral absorption
•Can be administered orally
•Cefradine is first generation and orally active
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 -lactamases)
9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H S
HO2C N
H2N H Cephamycin C
O
N O NH2
O C
CO2H O
•Isolated from a culture of Streptomyces clavuligerus
•First -lactam to be isolated from a bacterial source
•Modifications carried out on the 7-acylamino side chain
9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H S
N
7 Cefoxitin
S O 3
N O NH2
O C
CO2H O
•Broader spectrum of activity than most first generation
cephalosporins
•Greater resistance to -lactamase enzymes
•Less metabolised by esterase enzyme (due to urethane)
9. Second Generation Cephalosporins
9.2 Oximinocephalosporins
Me
O
N
H H H
S
C
N Cefuroxime
O O
N O NH2
O C
CO2H O
•Much greater stability against some -lactamases
•Wide spectrum of activity
•Useful against organisms that have gained resistance to penicillin
•Not active against P. aeruginosa
•Used clinically against respiratory infections
9. Second Generation Cephalosporins
9.2 Oximinocephalosporins
Cefuroxime axetil
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10. Third Generation Cephalosporins
Oximinocephalosporins
R
Me
CH2OCOMe Cefotaxime
O H Ceftizoxime
Aminothiazole N Me
ring H H H
S
N N CH2S N
C N Ceftriaxone
H2N
N
S O OH
N
O R O
CO2H
•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 (reserve troops) –
Injectable as they are orally inactive
10. Third Generation Cephalosporins
Oximinocephalosporins
Me
Me CO2H
O
N
H H
N
H
S Ceftazidime
C
S
N O
N N
H2N O
CO2
•Injectable cephalosporin
•Excellent activity vs. P. aeruginosa and other Gram -ve bacteria
•Can cross the blood brain barrier
•Used to treat meningitis
11. Fourth Generation Cephalosporins
Oximinocephalosporins
Me
O R
N Me
H H H
S N Cefipime
N N CH2
H2N C
S O
N
O R Cefpirome
CH2 N
CO2H
•Zwitterionic compounds
•Active vs. Gram +ve cocci and a broad array of Gram -ve bacteria
•Active vs. P. aeruginosa
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Orally active First and Second-Generation cephalosporin
Cefradine – 1st generation
Cefaclor – 2nd generation Cefprozil – 2nd generation
Orally active third-generation cephalosporin
Cefixime
Cefdinir Ceftibuten
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