Lecture 1.P2,Lecture 2 P1
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Transcript Lecture 1.P2,Lecture 2 P1
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
1
CH3
2
S
5
6
C HN
CH3
N
3 COOH
O 7 4
O
Classes of -lactam antibiotics:
(1) Penicillin.
(2) Cephalosporin.
(3) Novel -lactam antibiotics.
5
R
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
17
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.
20
[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
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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 .
28
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
H3 C
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
R
esterase
S
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
Opened chain
N
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