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CEPHALOSPORINS
O
R
C
H
N
H
H
S
N
OAc
O
CO2H
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
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)
3. Properties of Cephalosporin C
H H
N
H2N
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
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
O
Me
5. SAR of Cephalosporins
H H
N
R
7
8
O
H
6
5
N
S
1
4
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
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
Enzyme
Note
The acetoxy group acts as a good leaving group and aids the mechanism
CO2H
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
Me
O
H
N
O
O
O
7-ACA
•7-ACA not available by fermentation
•7-ACA not available by enzymatic hydrolysis of cephalosporin C
•Generated by a chemical hydrolysis
S
CO2H
C
O
Me
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 blactam ring
H
N
R1
H
H
S
PCl5
7
O
N
4
O
3
R1
N
H
R1
ROH
Cl
OAc
H
H2O
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
O
CO2H
Range of cephalosporins
8. First Generation Cephalosporins
Cephalothin
H H
N
7
S
O
H
S
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
N
7
S
O
H
H H
N
S
3
N
S
OAc
Metabolism
O
O
H
S
N
OH
O
CO2H
CO2H
•Less active
•OH is a poorer leaving group
Strategy
Replace the acetoxy group with a metabolically stable leaving group
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
8. First Generation Cephalosporins
Cefalexin
H2N
H
H H
N
7
O
H
S
3
N
Me
O
CO2H
•The 3-methyl group is a poor leaving group
•Methyl group is bad for activity but aids oral absorption
•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
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
S
H2O2
Me
Me
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
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 blactamases)
9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H
N
HO2C
H2N
H
S
Cephamycin C
O
N
O
O
CO2H
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
NH2
9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H
N
7
S
O
S
Cefoxitin
3
N
O
CO2H
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
9. Second Generation Cephalosporins
9.2 Oximinocephalosporins
Me
O
N
C
O
H H
N
O
H
Cefuroxime
S
N
O
O
CO2H
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
10. Third Generation Cephalosporins
Oximinocephalosporins
R
Me
Aminothiazole
ring
O
N
H 2N
S
N
C
H H
N
O
H
Cefotaxime
Ceftizoxime
CH2OCOMe
H
Me
S
CH2S
N
N
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
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
11. Fourth Generation Cephalosporins
Oximinocephalosporins
R
Me
O
N
H 2N
S
Me
N
C
H H
N
O
H
CH2
S
N
N
R
O
CO2H
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
COMPULSORY READING FROM TEXTBOOK – WILSON AND GISVOLD
• PAGES - 278 TO 293
•
EXAMPLES: ALL EXAMPLES LISTED [PAGES 286 – 293]
COMPULSORY READING FROM TEXTBOOK – PATRICK
•
THE ENTIRE SECTION ON CEPHALOSPORINS
IN CHAPTER 19