Download lactam Antibiotics - Millennium Organization

Lectures 2, 3
Medicinal Chemistry 1
PC 509
Prof. Dr/ Ghaneya Sayed Hassan
[email protected]
1
Antibiotics
• Definition of antibiotics:
Chemical compounds produced by a living m.o. and capable of
inhibiting life process of other m.o.
• If kill m.o.  Bactericidal, if just inhibit its growth  Bacteriostatic.
• There are compounds with anti-bacterial activity but not antibiotic [as
sulfonamides]  because they are fully synthetic compounds 
named anti-bacterial drugs.
Classification of antibiotics:
(1) According to M.O.A: inhibit cell wall, act on protein
synthesis…
(2) According to spectrum of activity: Broad spectrum,
narrow spectrum.
(3) Chemical classification: -lactams & non--lactam
2antibiotics.
Antibiotics
Definition:
Microbial metabolites, semi-synthetics or synthetic analogues which
inhibit [in small doses] growth & survival of m.o. without serious toxicity
on the host.
Classified into:
B-lactam Antibiotics
 Penicillins.
 Cephalosporins.
 Novel  -lactam
antibiotics.
3
Non B-lactam Antibiotics
 Tetracyclines.
 Aminoglycosides.
 Macrolides.
 Miscellaneous
[Chloramphenicol]
-lactam antibiotics
-lactam ring [4-membered cyclic amide]: is the main part of penicillin
and cephalosporin structures.


-lactam ring = Azetidinone
NH
O
N
-lactam ring
4
O
N
O
-lactam ring
4
Fundamental structural requirements for classical -lactam
antibiotics:
(1) Highly strained fused -lactam structure.
(2) Free carboxylic group.
(3) One or more substituted amino side chain.
(4) Optimal activity in -lactam requires a side chain with a
hydrogen-bonding group & some structural features that 
chemical reactivity of -lactam ring.
B-lactam ring
O
Classes of  -lactam antibiotics:
(1) Penicillin.
(2) Cephalosporin.
(3) Novel  -lactam antibiotics.
5
R
C HN
O
6
5
N
7 4
1
CH3
S 2
CH3
3
COOH
M.O.A. of -lactam antibiotics:
[Inhibitors of cell wall synthesis]
NAG
NAM
L-Ala
L-Ala
D-Glu
D-Glu
L-Lys
Gly
Gly
Gly
Gly
L-Lys
Gly
D-Ala
D-Ala
D-Ala
D-Ala
NAG
L-Ala
D-Glu
D-Glu
D-Ala
Gly
Gly
Gly
Gly
Gly
Gly
Gly
L-Lys
Gly
Gly
carboxy peptidase
B-lactams
Sugar Backbone
NAG
NAM
L-Ala
L-Lys
Gly
Sugar Backbone
Transpeptidase
D-Ala
NAM
NAG
NAM
Gly
Gly
Gly
Gly
Gly
D-Ala
Cross - Linking
6
https://www.youtube.com/watch?v=qBdYnRhdWcQ
M.O.A. of -lactam antibiotics:
[Inhibitors of cell wall synthesis]
β-lactam antibiotics cause:
(1) irreversible inhibition of transpeptidase enzyme
by acylation of OH of serine amino acid residue on it 
no cross-linkage rigidity  leakage of important
components and entrance of water  swelling and
rupture of cell  [Bactericidal effect] in the growth phase.
(2) -lactams also inhibit D-alanine carboxypeptidase
[responsible for cleavage of D-ala.]
7
The β-lactam is able, because of a structural resemblance to the Dalanyl-D-alanine segment, to compete with the catalytic process and
form a transient pencilloyl-enzyme complex
8
[I] Penicillins
Structure:
Highly unstable Bicylic system:
β-lactam ring [Azetidinone] +
Thiazolidine ring
B-lactam ring
O
R
C HN
O
6
5
N
7 4
Their structure biosynthesized by
m.o. from the two amino acids:
cysteine & valine forming 6Amino Penicillanic Acid [6-APA].
3
S
CH3
CH3
N
O
Thiazolidine ring
COOH
H2N
Cysteine
9
1
CH3
S 2
CH3
COOH
Valine
R for Rectus ,Latin for right,)S (for Sinister, Latin for left)
Stereochemistry:
• With three chiral carbons:
theoretical 8 isomers.
• The only active is 
C3 [S] , C5 [R] & C6 [R].
O
R
O
4-thia-1-azabicyclo [3.2.0] heptanes.
6
N
7
1
O
S
10
N
O
R
S
C HN
C HN
O
CH3
CH3
N
COOH
Penicillanic acid derivatives:
CH3
CH3
N
O
S
COOH
COOH
O
2
*
CH3
CH3
CH3
3
Penam derivatives:
[without
any substitutions]
*
N
O
R
CH3
S
*
Nomenclature:
4
5 S
C HN
COOH
Penicillin derivatives:
Physicochemical properties:
1- White or yellowish-white crystalline powders [sometimes Pen.G =
Crystalline Pen.]
2- Strongly dextrorotatory.
3- Relatively strong acidic [with pka around 2.65]  due to COOH group.
4- If compound with basic side chain  present as Zwitter ions.
5- Most penicillins used Na or K salts  water soluble salts.
6- Fused -lactam ring  highly reactive [due to strained amide bond]
 extremely susceptible to nucleophilic attack & electrophilic attacks.
7- They are inactivated by hydrolysis [especially in presence of heavy
metal salts, acids & bases]
8- They are also hydrolyzed by enzymatic action  acylase [amidase] &
-lactamase.
O
R
O
N
H
O
S
N
CH3
CH3
COOH
- R
alklaine medium [OH ]
B-lactamase enzyme
S
N
H
O
CH3
HN
OH
CH3
COOH
Penicilloic acid
11
Penicillin analogues = Semisynthetic penicillins
6-APA is now produced by hydrolysing penicillin G or
penicillin V with an enzyme (penicillin acylase) or by
fermentation
12
Semi-synthetic Penicillins:
• Natural penicillins  isolated from cultures of Penicillium chrysogenum &
Penicillium notatum fungi.
• To overcome drawbacks of natural penicillins [Pen.G]:
(1) Add precursors as phenoxy acetic acid to fermentation medium 
Penicillin V.
(2) Isolation of 6-Amino Penicillanic Acid [6-APA] in Beecham Research
Lab.[1957]  preparation of  no. of semi-synthetic compounds.
This is done by reaction of 6-APA with:
[1] Acid chloride [R-CO-Cl] / organic solvent / (Et)3N as proton acceptor.
[2] Acid anhydride [(R-CO)2O].
[3] Carboxylic acid [R-COOH] + DCC [N,N-dicyclohexyl carbodiimide] at
R.T.
N
13
C
N
SAR:
amide is essential
Stereochemistry of bicyclic system relative
to acylamino is important is essential
S isn't essential
O
R
C
HN
H
H
S
N
O
CH3
CH3
COOH
free COOH is essential
strained B-lactam is essential
Bicylic system is important --------> other cycle confers strain on
B-lactam ring & so, increase its activity [ also increase its instability]
Substituents above the plane of the steroid are described as beta and are
shown as a solid line (
or
);
those below the plane are described as alpha and are shown by a broken line
(
or ---)
14
Penicillin G [Benzyl Penicillin]
O
H2C
S
C HN
CH3
N
O
CH3
COOH
Properties:
• The PROTOTYPE [parent compound] [lead compound].
• Discovered by chance.
• Active ≠ G+ve bacilli [Staph., gonorrhoea] & G-ve cocci.
• Non-toxic [selective].
Serious limitations:
(1) Short duration of action rapidly excreted from kidney [need
injection /4 hrs]
(2) Ineffective orally  stomach acidity-sensitive & poorly absorbed
from GIT.
(3) Bacterial resistance by Penicillinase [-lactamase].
(4) Narrow spectrum of activity [active mainly ≠ G+ve with 
15 activity ≠ G-ve].
[i] Acid resistant penicillins
Penicillin G is acid-sensitive due to:
(1) Small angle & torsional strains [highly strained -lactam ring  relieve
strain by opening in acidic medium]
(2) Carbonyl group in -lactam ring is highly sensitive to Nu attack [not
behave as normal tertiary amide which is resistant to Nu attack].
(3) Acyl group in the side chain  attack -lactam ring.
Ph H2C
C
..
HN
O
S
N
O
CH3
CH3
COOH
H
+
Ph H2C
C
N
S
O
N
O
CH3
CH3
COOH
unstable intermediate
To overcome acid sensitivity:
• The first two factors can't be treated since
•-lactam is the essential moiety which
•can't be replaced; the only factor
•we can overcome is the third [acyl chain].
16
Ph H2C
C
N
S
O
HN
O
Inactive
CH3
CH3
COOH
This is done by tendency of acyl carbonyl group to act as a nucleophilie
by attachment of e-withdrawing group to it.
Penicillin V
[Phenoxy methyl penicillin]
O
O
H2C
S
C HN
CH3
N
O
CH3
COOH
Phenethicillin
[Phenoxy ethyl penicillin]
O
O
HC
CH3
C HN
O
CH3
CH3
N
Taken orally but less active than penicllin G
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S
COOH
[ii] -lactamase-Resistant penicillins
Action of -lactamase: [as action of alkaline medium]
Ph
CH2
C
NH
O
S
N
O
CH3
Ph
CH2
B-lactamase
CH3
C
HN
HO
COOH
S
O
O
HN
Penicilloic acid
[inactive]
CH3
CH3
COOH
To overcome this problem: Modify structure of
-lactam antibiotic: By placing a BULKY GROUP
on the side chain  shielding and steric
hindrance.
Methicillin:
-lactamase resistant but acid sensitive [NOT taken orally]
OMe
O
S
C HN
18
OMe
N
O
CH3
CH3
COOH
2,6-dimethoxy phenyl penicillin
With 1/5 activity of Pen.G &
inactive ≠ G-ve [Disadvantages]
Oxacillin
Cloxacillin
5-methy-3-phenyl isoxazol-4-yl
penicillin
O
N
Me O
O
O
CH3
S
C HN
3-(o-chloro phenyl)-5-methyl
isoxazol-4-yl penicillin
CH3
N
COOH
S
C HN
Cl
N
O
Me O
CH3
CH3
N
COOH
Flucloxacillin
3-(2-chloro-6-fluro phenyl)-5methyl isoxazol-4-yl penicillin
F
S
C HN
Cl
N
19
O
O
Me O
N
CH3
CH3
COOH
Isoxazole ring with two
roles:
1.Bulky group  -lactamase
resistant.
2.e-withdrawing group  acid
stable.
[iii] Narrow spectrum
Penicillin G with poor activity ≠ G –ve due to:
(1) Permeability barrier: G –ve bacteria with a coat on cell wall
composed of fats, sugars & proteins.
(2)  level of transpeptidase produced.
(3) Mutation of transpeptidase enzyme: producing form not antagonized
by penicillin.
(4) Presence & transfer of β-lactamase enzyme.
We notice that:
(1) Hydrophilic group on side chain:  activity ≠ G-ve & with little
change on activity ≠ G+ve bacteria.
(2) G-ve activity  if the hydrophilic group [NH2, OH, COOH] is
attached to C  to Carbonyl.
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[i] Class I Broad spectrum penicillins:
Taken orally [hydrophilic group is amino]
Amoxicillin
Ampicillin
O
O
HC
S
C HN
NH2
Phenyl glycine moeity
CH3
N
O
CH3
HO
HC
NH2
S
C HN
CH3
N
O
CH3
COOH
COOH
Ampicillin: is the 2nd most used penicillin in medicinal practice.
Amoxicillin: is analogue to ampicillin with phenolic group and better
absorption.
Proprieties:
(1) Active against G+ve & G-ve bacteria, but sensitive to –lactamase.
(2) Acid resistant due to amino group (can be used orally).
(3) Non toxic.
21
Side effects of Ampicillin:
Ampicillin is poorly absorbed from GIT 
disruption of gut flora  diarrhea.
This is due to bipolar nature [Zwitter ionic form]
 presence of free amino & free carboxylic group.
This is alleviated by using Prodrugs in which one
of its polar group is masked [this group removed
by metabolism releasing free drug].
When we make esters of ampicillin to improve its oral bioavailability:
It’s supposed to be cleaved by esterase enzyme to give free
ampicillin. But pencillin nucleus is very bulky that prevent approach of
esterase enzyme.
 So, we make Double ester in which carboxyl group is attached to
C3-monoesters of gemdiols [has 2nd OH group esterified by simple
carboxylic acid]
 That’s why we can’t make simple methyl ester as a prodrug for
ampicillin.
22
O
Pivampicillin
S
HC C HN
NH2
O
N
CH3
CH3
O
COO CH2
CH3
O C C CH3
CH3
Pivalic acid
(2,2-Dimethylpropanoic acid)
O
O
Talampicillin
HC
C HN
NH2
Bacampicillin
NH2
CH3 O
N
COO
O
O
HC
CH3
S
S
C HN
CH3
N
O
CH3
COO
O
CH
CH3
23
O
C
O
C2H5
► All of them are acyloxymethyl esters  susceptible to non-specific
esterase which act on 2nd ester group that is further away from
penicillin nucleus.
► The products formed from hydrolysis are unstable & decomposed
spontaneously to reveal free carboxylic acid & formaldehyde.
O
HC
C HN
NH2
H+
CH3
S
CH3
N
COO
O
O
CH2
O
C
CH3
C
CH3
Esterase
O
HC
HN
H3C
24
C
S
N
CH3
CH3
CH3
N
O
COOH
COO
CH2
+
CH3
Hetacillin
Pen
Pen
H
OH
COOH
Ampicillin
CH2=O
 Prodrug for ampicllin  by
blocking other polar group
[amino group].
It’s formed by condensation
of ampicillin with acetone.
Semi-synthesis of Ampicillin:
O
NH2
CH
O
COOH + Cl
Phenyl glycine
C
O
CH2
O
C
O
CH2
O
NH
S
O
N
C
OH
Pd / H2
NH
25
CH3
- CO2
S
N
O
COOH
CH2
Cl
S
C
CH3
CH3
COOH
O
Et
Ethyl chloro formate
[activating group]
CH3
O
CH3
NH
COOH
C
O
CH2
CH
6-APA
O
C
O
O
O
COOH
CH
O
CH
CH3
O
NH
O
O
N
CH
O
C
Benzyl oxy carbonyl chloride
[protecting group]
H2N
NH
NH
NH2
Ampicillin
CH
NH
O
S
N
O
CH3
CH3
COOH
Et
[i] Class II Broad spectrum penicillins:
 Hydrophilic group is COOH.
Carbenicillin
O
O
HC
C
COOH
Carfecillin
N
H
O
S
CH3
CH3
N
COOH
Active ≠ wide range of G-ve >
ampicillin.
More penicillinase resistant.
Active ≠ Pseudomonas
aeruginosa.
26
HC
C
COO
N
H
O
S
CH3
CH3
N
COOH
 Prodrug for Carbenicillin with improved
absorption [higher lipophilicity]
 We use aryl ester not alkyl ester  aryl
esters are more liable to hydrolysis due to
e-withdrawing and inductive effect of aryl
ring.
[iv] To prolong duration of action
[Latent penicillins]
Done by:
(1) Penicillin salts that are sparingly soluble in water.
(2) Penicillin amides.
(3) Penicillin esters.
(4) Substitution in the amino side chain.
We making suspension of  M.Wt amino salts  free penicillin is
released as compound dissolve & dissociate. [used as I.M.
injection]
Penicillin G procaine [1:1]
O
Ph
H2C
S
C HN
CH3
CH3
N
O
COO-
O
H2N
27
C
O
CH2 CH2 NH
CH2 CH3
CH2 CH3
Penicillin G benzathine
1:2
O
Ph
H2C
S
C HN
N
O
H3C
CH3
CH3 CH2
CH2 H3C
COO- NH2 CH2 CH2 NH2 OOC
Long Acting Penicillin Injection
‫حقن بنسلين طويل المفعول‬
Penicillin G Benzathine and Penicillin
G Procaine. A potent formulation
penicillin G that effectively kills
susceptible disease-causing bacteria .
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O
S
NH C
N
O
CH2
Ph
Novel -lactam Antibiotics
(-lactamase inhibitors)
 -lactamase inhibitors used in combination with -lactamase
sensitive penicillins for infections caused by -lactamase-producing
bacterial strains (e.g. Clavulanic acid, Sulbactam and Thienamycin).
Clavulanic acid
4
No 6-acyl amino side chain
6
7
O
5
OH
O
Z-configuraion
3
N
1
2
H
COOH
oxapenam [B-lactam+oxazolidine]
►1st natural -lactam without sulfur
► Isolated from Streptomyces clavuligerus in 1976.
► With weak anti-bacterial activity but Potent irreversible
inhibitor of most -lactamases.
29
SAR:
(1) -lactam ring.
(2) Double bond with Z configuration.
(3) No substitution at C6.
(4) Positions 2 & 5  R stereochemistry.
(5) Carboxylic group.
M.O.A:
(1) Irreversible inhibitor [Suicide substrate] for -lactamase.
(2) The drug fits active site of -lactamase  opening of -lactam
ring by serine residue on the enzyme [as in penicillins].
(3) Acyl enzyme intermediate  react further with another enzymic
nucleophilic group [amino group]  irreversible inhibition.
(4) This mechanism is carried out in presence of proton
donor/acceptor as histidine.
30
Amoxicillin and clavulanic acid
(Augmentin®)
Combination with Amoxicillin and Clavulanic acid
1- Decrease dose of amoxicillin
2- Increase spectrum of activity.
 Clavulanic acid has weak anti-bacterial
activity but Potent irreversible inhibitor
of most -lactamases.
Sulbactam
O
O
S
CH3
CH3
N
O
COOH
Semisynthetic ß-lactamase inhibitors
e.g.
sulbactam (penicillanic acid sulphone)
(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-bicyclo[3.2.0]heptane-2-carboxylic
31
acid –4,4-dioxide
Synthesis of Sulbactam
H
H
Br
S
H2N
N
CH3
CH3
O
(1) NaNO2
(2) Br2
S
Br
N
O
O
OH
O
H
CH3
KMnO4
CH3
OH
6-APA
Br
Br
HO O
S CH3
N
O
O
HO O
S CH3
10% Pd / C
CH3
N
O
O
OH
Tazobactam
-1,2,3-Methyl-7-oxo-3-(1H-3-)(2S,3S,5R)
triazol-1-ylmethyl)-4-thia-1-azabicyclo
[3.2.0]heptane-2-carboxylic
acid 4,4-dioxide
32
CH3
OH
Sulbactam
Sultamicillin
Saltum®, Unasyn®
Sultamicillin is an oral form
of the antibiotic combination
)codrug or mutual prodrug (
ampicillin/sulbactam .
It contains esterified
ampicillin and sulbactam
Sultamicillin increased the absorption and
decreased the chances of diarrhoea and dysentery .
33
Thienamycin
[Anti-bacterial + -lactamase inhibitor]
Opposite to penicillins
carbapenam
OH
H
H3C
H
H
N
O
S
CH2 CH2 NH2
endocyclin double bond
COOH
► Isolated from Streptomyces cattleya.
► Potent with extra-ordinary broad range of activity ≠ G+ve & G-ve
including Pseudomonas.
► With  toxicity &  -lactamase resistance.
► With poor metabolic & chemical stability.
34
Cephalosporins
35
First one discovered is Cephalosporin C [1948] from fungus obtained
from sewer water on island of Sardinia [by chance as penicillin G]
H2N
Dihydrothiazine ring instead of thiazolidine ring in penicillins
O
CH
(CH2)3 C HN
HOOC
S
O
N
CH2
O
high polar side chain
4.
5.
36
C
CH3
COOH
Advantages [over Penicillin G]
1.
2.
3.
O
Non-toxic
↓ risk of allergy.
More stable in acidic medium
[less ring strain]
Higher penicillinase resistance.
Good activity ≠ G-ve & G+ve.
Disadvantages
1.
2.
3.
Difficult to isolate & purify [with
highly polar side chain]
Lower potency [less strained
ring]
↓ absorbed orally.
Nomenclature:
IUPAC name:
5-Thia-1-azabicyclo[4.2.0] octane
Cepham:
1
7
6
8
N
5
O
1
S
7
2
8
3
Cepham
37
3
4
7-Amino Cephalosporanic acid [7-ACA]
S
O
O
O
COOH
Use Cephem & refer to substitution at
C3,4,7
H2N
S
O
2
Cephem
Cephalosporanic acid:
N
S
N
5
O
4
6
C
N
CH3
O
O
C
CH3
COOH
Use cephalosporanic acid & refer to
substitution at C7
Synthesis of 7-ACA:
7-ACA prepared from cephalosporin C by chemical hydrolysis. This is
not an easy task. After all, a secondary amide has to be hydrolyzed in
the presence of a highly reactive B-lactam ring. Normal hydrolytic
procedures are not suitable and so a special method had to be worked
out
O
R'-O
Cl
HN
N
S
R
N
OAc
O
COO
PCl5
Me
H 2O
N
COO
Me
imino chloride
OAc
R
Cl
O
COOH
7-ACA
38
Si
Me
Me
R'-OH
Acylation
S
R
N
OAc
O
COO
Me
imino ether
O
S
N
OAc
O
Protected Cephalosporin C
H2 N
R
Me
Si
N
S
range of cephalosporins
Si
Me
Me
Me
Classes of Cephalosporins
1)
Based on route of administration:
I- Oral cephalosporins.
II- Parentral cephalosporins.
3-Acetoxy methyl side chain:
By metabolism → alcoholic group → Lactone formation [loss activity +
poor absorption].
O
O
HN
R
S
HN
O
N
CH2
O
O
C
CH3
S
R
esterase
N
COOH
COOH
O
[active]
spontaneous
lactonization
[acidic]
HN
R
S
N
O
O
39
CH2
O
[inactive]
O
OH
2) Based on Generation system:
[I] 1st Generation Cephalosporins
- Introduced in clinical use in 1960 - 1970.
- With narrow spectrum of activity.
- ß-lactamase resistant [but not to G-ve bacteria].
- With short half life & poor ability to penetrate cerebrospinal fluid.
O
H2C
Cephalothin
C HN
S
S
O
N
CH2
O
O
C
CH3
COOH
Cephalexin [Ceporex®]
Cefadroxil [Duricef®]
Cephradine [Velocef®]
O
HC
C HN
HO
NH2
N
CH3
O
COOH
O
O
S
HC
C HN
NH2
S
N
CH3
O
COOH
40
Good for absorption
Usually bad for activity
HC
C HN
NH2
S
N
CH3
O
COOH
[II] 2nd Generation Cephalosporins
• Introduced since 1970 till the present.
• Spectrum as 1st generation, but more active ≠ G-ve.
• More resistant to ß-lactamase.
• Half lives similar to 1st generation, but penetrate better into
cerebrospinal fluid.
O
HC
Cefuroxime
C HN
NH2
(parentral agent)
N
COOH
Cefaclor
O
S
HN
O
N
O
NH2
O
HO
41
Cl
O
OCH3
N
S
O
O
oral agent
Cefonicid
Cephamandole
O
O
HC
C HN
OH
HC
S
N
N
CH2 S
O
COOH
N
N
N
CH3
C HN
OH
S
N
N
CH2 S
O
COOH
N
N
N
CH2
SO3H
OH on -carbon  succeed in
SO3H   lipophilicity  NO CSF
cephalosporins NOT in
penetration.
penicillins
42
[III] 3rd Generation Cephalosorins
• Introduced in 1980s, most of them are semi-synthetic
derivatives of cephalosporin C.
• With good stability ≠ ß-lactamase & with broader spectrum.
• Some of them active ≠ Pseudomonas.
• Taken I.M. or I.V.
• very expensive.
• Subdivided according to structure of side chain into:
1- Cephalosporins with amino thiazolyl oximino moiety.
2- Cephalosporins with different acyl residues.
43
1) Cephalosporins with amino thiazolyl oximino moiety
Cefotaxime [Cefotax®]
Cefmenoxime
OMe
OMe
H2N
N
N
O
C
C HN
H2N
S
S
N
N
N
O
C
C HN
S
S
S
N
O
COOH
N
H3C
O
N
CH2
O
N
O
C
CH3
COOH
N
Oxime ether group → increase
B-lactamase resistance.
Paranetrally [W?]
2) Cephalosporins with different acyl residues
N
Opened chain
C
Cefivitril
O
C HN
S
S
N
N
CH2
O
44
COOH
S
N
H3C
N
N
OCH3
N
Cefotaxime
C
S
C
HN
N
Claforan®
H2N
O
O
H
S
N
HO
O
O
CH3
O
• Cefotaxime was the first third-generation cephalosporin
to be introduced.
• It possesses excellent broad-spectrum activity against
Gram-positive and Gram-negative aerobic and
anaerobic bacteria.
• Many β–lactamase-producing bacterial
strains are sensitive to cefotaxime.
45
The fourth-generation cephalosporins
• The fourth-generation
cephalosporins show some slight
further advantages.
• They have similar antibacterial
activity with the third generation ,
but more stable to -lactamase.
• There is a quaternary ammonium
group at position 3
• Fourth-generation cephalosporins are
zwitterions that can penetrate the
outer membrane of gram-negative
bacteria.
• They also have a greater resistance to
beta-lactamases than the third46
generation cephalosporins
2007
Cefpirome
Cefepime
The fifth-generation cephalosporins
Fifth-generation cephalosporins are effective against MRSA
(methicillin-resistant Staphyloccus aureus) and enterococci.
Ceftolozane
Ceftolozane is a new option for treatment of Complicated
Intra-abdominal Infections (cIAI), and
Complicated Urinary Tract Infections (cUTI(
Zerbaxa®(ceftolozane/tazobactam(
47
February 01, 2015
[IV] Cephamycins (= 7-methoxy cephalosporins)
► Parent is Cephamycin C → isolated from Streptomyces clavuligerus
[the 1st ß-lactam isolated from bacterial source].
► By modification of side chain → Cefoxitin [Broader spectrum than
most cephalosporins due to high resistance ≠ ß-lactamase].
► ↑ ß-lactamase resistance is due to steric hinderance of extra methoxy
group.
► Cephamycins possess  methoxy group at the 7-alpha position
► Cephalosprins and Cephamycins are cephem derivatives
O
H2 C
HOOC
H
C
O
(CH2)3 C
NH
NH2
OMe
Cephamycin C
HOOC
48
O
Cephalosporin C
C
Cephalothin
CH2
S
N
O
O
COOH
O
C
NH2
COOH
CH (CH2)3
O
CH2
O
N
O
C HN
S
N
S
O
H2N
C HN
S
O
CH2 O C CH3
COOH
Cefoxitin
O
S
H2C
C HN
OMe
S
O
N
CH2
O
COOH
O
C
NH2
CH3