Transcript B. Cephalosporins, monobactams and carbapenems

β-lactamase inhibitors
 Almost all have weak antibacterial activity.
 Important in combination with penicillins sensitive to
β-lactamase degradation.
 Clavulanic acid is the first one of this class.
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Natural product from streptomyces.
Has a powerful and irreversible inhibition of βlactamase enzymes because it will covalently bind to
two positions in the active site.
Normally used in combination with
amoxicillin and other β-lactamase
sensitive penicillins
SAR for β-lactamase inhibitors
 β-lactam ring is essential.
 The enol ether have a rule in binding.
 The elkene moiety should have Z configuration which
is much more active than the E isomer.
 No substitution at C6.
 R stereochemistry at C3.
 Carboxylic acid at C3 is essential.
Cephalosporins.
 The first agent discovered was cephalosporin C, obtained
from the fungus cephalosporium acremonium.
 1/1000 the antibacterial activity of penicillin G.
 Has the same mechanism of action as penicillins (inhibits
cell wall cross linking).
 Has greater stability toward acid and β-lactamase.
SAR of cephalosporins
 The bicyclic system is essential.
 The carboxylic acid at C4 is essential.
 Acylamino group at C7 is essential.
 Acetyloxy group at C3 is important and act as a leaving
group when the molecule binds to transpeptidase.
Synthesis of Cephalosporins
 Unlike 6-APA, 7ACA was difficult to isolate and purify.
 Instead, 7ACA was synthesized from cephalosporin C
as follows
st
1
Generation Cephalosporins
 Have lower activity than penicillin but they have
broader spectrum action.
 Still susceptible to β-lactamase degradation.
 Steric shield helped to improve stability toward β-
lactamase degradation but proved to reduce
antibacterial activity.
st
1
Generation Cephalosporins
 Have the good leaving group, pyridinium ion.. This
improved activity.
 This group is not hydrolysable compared to the acetyloxy
group found in cephalothin.
 Poorly absorbed from the gut because it will be ionized all
the time.
 Only given parenterally.
nd
2
Generation Cephalosporins
 They have methoxy group at C7 which make them
active against the resistant strains.
 They have a carbamate group at C3 that increase
stability toward hydrolysis compared to the acetyloxy
group found in 1st generation derivatives.
nd
2
Generation Cephalosporins
 Other agents are the oximinocephalosporins:
 Have the iminomethoxy group at the α-carbon in the
acyl side chain, this increased stability toward βlactamase.
rd
3
Generation Cephalosporins
 Here the aminothiazole ring has replaced the furan
ring of cefuroxime:
 This enhanced the penetration through the outer
membrane of gram –ve bacteria,
 Increase the affinity for transpeptidase.
 Not recommended as first
line therapy to prevent the
rapid development of resistance.
rd
3
Generation Cephalosporins
 Cefdinir (Omnicef®):
 It has a broad spectrum activity.
 More active on gram –ve bacterial
infections such as respiratory, skin and soft tissues
infections.
 Estimated oral bioavailability is 20-25% (WHY?).
 LogP = 0.02
 pKa = 3.27
th
4
Generation Cephalosporins
 They have a positively charged group at C3 which become a
good leaving group during the binding with
transpeptidase.
 They are more polar than the old generation, better
penetration for the outer membrane of gram –ve bacteria.
 More stable toward β-lactamase.
New generation Cephalosporins
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Cephtobiprole
5th generation cephalosporin (2008).
Only given IV (Why?).
Resistant to staphylococcal β-lactamase (Why?).
activity against methicillin-resistant S. aureus, penicillinresistant S. pneumoniae, P. aeruginosa, and Enterococci.
New generation Cephalosporins
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Cefsulodin
3rd generation cephalosporin.
has very specific activity against P. aeruginosa.
limited activity against Gram-positive bacteria and
anaerobic bacteria.
Is not clinically used nowadays (difficult to purify during
synthesis).
New generation Cephalosporins
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Ceftaroline
5th generation cephalosporins.
It retains the activity of later generation cephalosporins
having broad spectrum activity against Gram -ve and gram
+ve bacteria especially on resistant strains.
Approved for clinical use in USA in 2010.
Still in clinical trials (phase III).
New generation Cephalosporins
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Cefmenoxime
3rd generation cephalosporins.
It is mainly active on gram –ve bacteria.
Only available as intramuscular injections.
LogP = - 0.87
New generation Cephalosporins
Predict its pharmacokinetic and activity profile?
Carbapenems
 No thiazolidine or dihydrothiazine ring.
 They have two strained rings which decrease the
chemical stability as well as acid stability.
 The inverse stereochemistry at C6 and the presence of
hydroxyl group increase stability toward β-lactamase
enzymes.
 They have broad spectrum activity.
Monobactams
 It has a limited activity against gram +ve bacteria.
 Because it does not have the fused ring system, Aztreonam
is believed to have different mechanism of action..
 highly polar structure which reduce the oral
bioavailability… it is recommended to be given parenterally