β-lactamase inhibitorsAlmost all have weak antibacterial activity.Important in combination with penicillins

sensitive to β-lactamase degradation.Clavulanic acid is the first one of this class.

Natural product from streptomyces. Has a powerful and irreversible inhibition of β-

lactamase 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

6

7 N4

5

3

2O

1

OCOOH

OHH

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.

6

7 N4

5

3

2O

1

OCOOH

OHH

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.

7

8 N5

6

4

3

2S1

O COOH

O

O

HN

O

H2NH

COOH

7-aminocephalosporinic acid (7-ACA)

SAR of cephalosporinsThe 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.7

8 N5

6

4

3

2S1

O COOH

O

O

HN

O

H2NH

COOH

Enzyme O

H

7

8 N5

6

4

3

2S1

O COOH

O

O

HN

O

H2NH

COOH

O

Enzyme

N

S

COOH

HN

O

H2NH

COOH

O

Enzyme

O

OH

O2

Synthesis of CephalosporinsUnlike 6-APA, 7ACA was difficult to isolate

and purify.Instead, 7ACA was synthesized from

cephalosporin C as follows N

S

O COOSiMe3

O

O

HN

O

R PCl5N

S

O COOSiMe3

O

O

N

Cl

R ROHN

S

O COOH

O

O

N

OR

R

H2O

imino ether

N

S

O COOH

O

O

H2NR2 Cl

O

N

S

O COOH

O

O

HNR2

O

1st Generation CephalosporinsHave 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.

N

S

O COOH

O

O

HN

OS

Cephalothineasily hydrolysed to give the inactive alcohol metabolitemainly given parenterally

N

S

O COOH

HN

O

NH2

Cephalexinless active than cephalothin due to the poor leaving methyl groupbetter oral bioavailability than cephalothin

1st 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.

N

S

O COOH

HN

OS

N

Cephaloridine

2nd Generation CephalosporinsThey 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.

N

S

O COOH

HN

OS

OO

NH2

O

CefoxitinBroad spectrum in activitygreater resistance to -lactamasemore stable orally toward hydrolysis

2nd Generation CephalosporinsOther agents are the oximinocephalosporins:

Have the iminomethoxy group at the α-carbon in the acyl side chain, this increased stability toward β-lactamase.

N

S

O COOH

HN

OO

ONH2

O

NO

Cefuroxime

3rd Generation CephalosporinsHere 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.

N

S

O COOH

R

HN

OS

N

NO

R = H ceftizoxime

R =

H2N

O

O

cefotaxime

R = S NH

NHN

O

OH

Ceftriaxone

3rd Generation CephalosporinsCefdinir (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 = 0.02pKa = 3.27

N

S

O COOH

HN

OS

N

NHO

H2N

4th 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.

N

S

O COOH

HN

OS

N

NO

H2N

N

Cefipime

N

S

O COOH

HN

OS

N

NO

H2N

N

Cefpirome

New generation Cephalosporins

Cephtobiprole5th generation cephalosporin (2008).Only given IV (Why?).Resistant to staphylococcal β-lactamase (Why?).activity against methicillin-resistant S. aureus,

penicillin-resistant S. pneumoniae, P. aeruginosa, and Enterococci.

N

S

O

HN

O

NS

NH2N

NHO

COOH

N

ONH

New generation Cephalosporins

Cefsulodin3rd 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).

N

S

O

HN

O

COOH

S OHOO

N

NH2

O

New generation Cephalosporins

Ceftaroline5th 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).

N

S

O

HN

O

COOH

S N

SN

NO

NS

NHNPO

HOHO

New generation Cephalosporins

Cefmenoxime

3rd generation cephalosporins.It is mainly active on gram –ve bacteria.Only available as intramuscular injections.LogP = - 0.87

N

S

O

HN

O

COOH

S NN

NN

NO

S

NH2N

New generation Cephalosporins

N

S

O

HN

O

COOH

NO

S

NH2N

OH

O

Cefixime

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.

N

O

S

R

HOH

COOH

R = NH2 Thienamycin

R = NHCH=NH imipenem

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

N

O

HN

O

NO

COOH

SN

H2NSO3

Aztreonam