‫‪Pharmaceutical Organic Chemistry 1‬‬

‫)‪(PC101‬‬
‫)‪Credit hours: 3 (2+1‬‬
‫‪Ass. Prof. Mamdouh Fawzy Ahmed Mohamed‬‬
‫‪Sohag University‬‬
‫‪Faculty of Pharmacy‬‬
‫‪Pharm. Chem. Dep.‬‬

‫د‪ /.‬ممدوح فوزى احمد محمد‬

‫استاذ مساعد الكيمياء الصيدلية ‪ -‬كلية الصيدلة – جامعة سوهاج‬
‫رئيس قسم الكيمياء الصيدلية‬
‫ووكيل كلية الصيدلة لشئؤن الدراسات العليا والبحوث‬
Learning Objectives
 Important definitions
Chemotherapy is the killing of a living organism (or living cell) whether being bacteria,
fungi, protozoa, or virus or even cancer.

Antimicrobial drugs: are the drugs used for treatment of infectious diseases the
killing of a living organism (or living cell) whether being bacteria, fungi, protozoa,
or virus … etc.so, without cancer we can not say chemotherapy.

Antimicrobial drugs : can be classified into

1. Therapy for bacterial infections
2. Therapy of special infections such as viral, parasitic, protozoal, fungi …etc.

Bacteria are prokaryotic cells. Some bacteria are pathogenic to humans and can cause
serious infections; the principal treatment of infections is with antibiotics
 Bacterial cell wall structure
Gram-positive Bacterial Membrane Structure
Gram-positive Membrane
The lipid bilayer cell membrane of most of the
Gram-positive bacteria is covered by a thick
peptidoglycan layer

Peptidoglycan Layers

Cytoplasmic Membrane
 Bacterial cell wall structure
Gram ve bacterial cell
wall
 Bacterial cell wall structure
Gram-negative Bacterial Membrane Structure
Gram-negative bacteria are surrounded by two membranes.
The outer membrane functions as an efficient permeability barrier containing
lipopolysaccharides (LPS) and porins. it is difficult for penicillin to invade Gram -ve bacterial
cell wall because of the fatty coating which acts as a barrier to polar, hydrophilic penicillin
molecule (-COO-). The only way in which penicillin can negotiate such a barrier is through
the hydrophilic porin channels in the outer coating.

Cell Membrane

Peptidoglycan

Cytoplasmic Membrane
Bacterial cell wall structure

Gram –ve cell wall structure

 Gram-positive and Gram-negative

Gram-positive bacteria are bacteria that give a positive result in

the Gram stain test. Gram-positive bacteria take up the crystal
violet stain used in the test, and then appear to be purple-
coloured when seen through a microscope. This is because the
thick peptidoglycan layer in the bacterial cell wall retains
the stain after it is washed away from the rest of the sample.

Gram-negative bacteria are a group of bacteria that do not retain

the crystal violet stain used in the Gram staining method, because
their peptidoglycan layer is too thin to retain the stain and is
sandwiched between an inner cytoplasmic cell membrane and
a bacterial outer membrane.
 CLASSIFICATION OF ANTIMICROBIAL DRUGS

A. According to source:

B. According to the effect on microorganisms:

C. According to mechanism of action:

D. According to antimicrobial spectrum:

E. Chemical Classification of Antibiotics

 CLASSIFICATION OF ANTIMICROBIAL DRUGS

A. According to source:

1. Natural compounds: e.g. penicillin, chloramphenicol.

2. Synthetic compounds: e.g. sulfonamides, quinolones.

3. Semisynthetic compounds: e.g. ampicillin.

 CLASSIFICATION OF ANTIMICROBIAL DRUGS

B. According to the effect on microorganisms:

1. Bactericidal agents: that kills the microorganism e.g. penicillin.

2. Bacteriostatic agents: arrest growth of the microorganism e.g. sulfonamides.

Mechanism of action of Antibiotics
Mechanism of action of Antibiotics
 CLASSIFICATION OF ANTIMICROBIAL DRUGS

C. According to mechanism of action:

1. Agents act by inhibition of cell wall synthesis: e.g. penicillin.

2. Inhibition of cell membrane function e.g. amphotericin B and azoles.

3. Agents act by inhibition of nucleic acid synthesis: e.g. quinolones.

4. Agents act by inhibition of protein synthesis:

 By acting on ribosomal 30 S subunit e.g. aminoglycosides.

 By acting on ribosomal 50 S subunit e.g. macrolides.

5. Agents act by inhibition of bacterial metabolism: .g. sulfonamides

CLASSIFICATION OF ANTIMICROBIAL DRUGS
Antibiotic Mechanisms of Action
Mechanism of action of Antibiotics
Mechanism of action of Antibiotics
 CLASSIFICATION OF ANTIMICROBIAL DRUGS

D. According to antimicrobial spectrum:

A. Narrow spectrum drugs:

 Drugs affect mainly Gram +ve spp. e.g. benzyl penicillin.

 Drugs affect mainly Gram –ve spp. e.g. aminoglycosides.

B. Extended spectrum drugs: agents that affect Gram +ve & Gram –ve spp.

C. Broad spectrum drugs: agents act on wide range of Gram spp. and others

(protozoa) e.g. tetracyclines

 E. Chemical Classification of Antibiotics

-Lactams : Penicillins and Cephalosporins

Aminoglycoside : Streptomycin and Kanamycin.

Fused ring system : Tetracyclines.

Macrolides : Erythromycin

Polypeptide : Polymixin.

Polyene : Amphotericin.

Miscellaneous : Chloramphenicol.
 1. -LACTAM ANTIBIOTICS
Chemical nuclei constituting the backbone of different -
lactam antibiotics:
S O

N N N
O O
1. Penam O
2. Carbapenam 3. Oxapenam

N N
N O
O O
4. Penem 5. Carbapenem 6. Monobactam
S O

N N N
O O O
7. Cephem 8. Carbacephem 9. Oxacephem
Penam (structure No.1) constitutes the
backbone of all penicillins S

Azitidlone N
O
Penam
Thiazolidine
Cephem (structure No.7) constitutes the
backbone of all cephalosporins
S

N
O
Cephem
Thiazoline
 PENICILLINS

In 1928, Alexander Fleming made a crucial discovery

that led to the production of Penicillin after leaving
some used culture plates unattended for several
weeks, he arrived back from his vacation to find
fungus growing on them. On one plate, the
Staphylococcus aureus that had been cultured there
appeared to be inhibited by the fungus that had
appeared. This fungus was found to be Penicillium
notatum and everywhere it appeared on the plate,
the bacterial growth was inhibited.
 PENICILLINS

With the help of Howard Florey (a pathologist) and

Ernst Chain (a biochemist), the -lactam antibiotic,
penicillin, was purified and produced on an industrial
scale for widespread use for the first time in the early
1940’s.
Penicillins contain a highly unstable bicyclic system
consisting of a four-membered -lactam ring fused to a
five-membered thiazolidine ring (penam).

A = -Lactam ring.
B = thiazolidine ring
 Nomenclature of Penicillins
named as penam derivatives:
e.g. Benzylpenicillin (Penicillin G)

6-Phenylacetamido-2,2-dimethylpenam-3-carboxylic acid.
penam

Penicillin G and V(PhenoBenzylPenicllin) are the only natural penicillins

NO synthetic penicilllin
or named as penicillanic acid derivatives
e.g. Ampicillin

6-[D(-)--Aminophenylacetamido]penicillanic acid.
Penicillanic acid
or named by trivial nomenclature

As derivatives of Penicillin

e.g. Ampicillin

D(-)--aminobenzylpenicillin.
 Classification of Penicillins
a) Natural Penicillins and b)Semisynthetic Penicillins

a) Natural Penicillins
They are commercially produced from the cultures of
Penicillium chrysogenum.
Benzylpenicillin (Penicillin G) is an example of the
natural penicillins.

H H
CH2 NH S CH3

N CH3
O O
COOH
 Properties of Benzylpenicillin
 Non toxic, the penicillins are amongst the safest drugs
known to medicine. has no anti staph effect
 Active only against Gram-positive bacteria (narrow
spectrum)
 Ineffective when taken orally, since it breaks down in
the acid of the stomach.
 Sensitive to all known -lactamases which are
produced by penicillin-resistant bacteria leading to the
catalytic degradation of penicillin and loss of
antibacterial properties.
 A relatively short duration of action.

 Allergic reactions are suffered by some individuals.

Essential Structure Features of Penicillins
 Strained -lactam ring. very essential
 Free carboxylic group.
 The bicyclic system.
 Acylamino side chain is essential
 The stereochemistry of the bicyclic ring with respect to the
acylamino side Chain.
 Sulfur is not essential.
Amide essential cis stereochemistry essential
H
O H H
C N S CH3
R
N CH3
O Free acid essential
COOH
lactam ring
essential

Bicyclic system essential

 Stability of Benzylpenicillin
The -lactam ring is highly strained and highly
active. Stabilization of the carbonyl group is
possible in tertiary amine, but is impossible in
the -lactam ring.

R .. R R
+
Tertiay C N R2 C N (resonance)
- R
Amide O O in tertiary amide
The -lactam nitrogen is unable to feed its lone
pair of electrons into the carbonyl since this
would require the bicyclic ring to adopt an
impossible strained flat system. As a result; the
lone pair of electrons is localized on the
nitrogen atom and the carbonyl group is far
more electrophilic than one would expect for
tertiary amide (no resonance structure in case
of -lactam).
Therefore, penicillin is easily attacked by acids
(Electrophilic) or bases (Nucleophilic), also by
amidase or -lactamase (penicillinase) enzyme.
Nucleophilic Attack (By OH¯)
Electrophilic Attack (By Gastric Acidity)

hydrolysis
Degradation products
H2O
Sensitivity of Penicillins to -Lactamases
-Lactamases are enzymes which catalyze the hydrolysis of -
lactam ring. The production of -lactamases by bacterial cell is the
most important contributing factor to the development of
penicillin-resistant strains of bacteria.
O
H H
R CO HN S R C N S
CH3 CH3

N CH3 O H N CH3
Nu O
COOH Nu : OH2 COOH
+
H

-lactamase -lactamase
R COHN S CH3

O HN CH3
OH COOH
Nu

-lactamase
Disadvantages of penicillin G include:
 A relatively short duration of action

 Acid liability.

 Sensitivity to ß-lactamases (penicillinases)

which will limit their effectiveness
 Narrow spectrum.
 The possibility of hypersensitivity reactions.
 b)Semisynthetic Penicillins
The production of semi synthetic penicillins from natural
penicillins could be produced by hydrolyzing
benzylpenicillin using penicillin acylase to give 6-APA.
The produced 6-APA is then acylated with a range of
acid chlorides in presence of triethylamine or sodium
bicarbonate.
 Types of Semisynthetic Penicillins
A. Acid Stable Semisynthetic Penicillins
B. -Lactamase Stable Penicillins
C. Extended-Spectrum Penicillins
D. Long acting Penicillins

Introduction of an electron withdrawing group in the -

position of the amide side chain decreases the nucleophilicity
of the side chain amide carbonyl oxygen towards participating
in -lactam ring opening. Examples are:
Phenoxymethylpenicillin Azidocillin
(Penicillin V) O O
H H
H H CH C N
O CH2 C N
N3

O O
However, the two drugs are still affected by -lactamases
 Types of Semisynthetic Penicillins
B. -Lactamase Stable Penicillins
One way of doing this, is to place a bulky group on the
side chain to sterically block the attack of -
Lactamase enzyme on the -lactam ring.
Methicillin Nafcillin
(2,6-Dimethoxyphenylpenicillin),
OMe
O H
H H
C N S CH3

OMe N CH3
O
COOH
methoxy considered as bulky
They have no electron withdrawing group on the side chain, so
they are acid sensitive and have to be administered by injection.
Further work eventually solved the problem of acid sensitivity
by incorporating into the side chain a five-membered
heterocyclic isoxazole ring carrying bulky substitution. This
ring acts as a steric shield and also to be electron withdrawing.
R O H
Oxacillin R = R`= H
C N S
Cloxacillin R = Cl, R`= H
Dicloxacillin R = R`= Cl
R` N Flucloxacillin R = Cl, R`= F
CH3 N
O O
COOH
Introduction of 6--methoxy
group to penicillins yields
derivatives which are highly OCH3
CH CONH
resistant to most bacterial - S CH3
lactamases. An example is COOH
Temocillin and is not absorbed S N CH3
O
orally and is supplied as sodium COOH
salt for parenteral administration.
 Types of Semisynthetic Penicillins
C. Extended-Spectrum Penicillins (aminopenicillins,
carboxypenicillins and ureidopenicillins)

1- Aminopenicillins
The introduction of an amino group in the -position of the
side chain of benzylpenicillin confers a high degree of acid
stability together with enhanced activity against some Gram
-ve bacteria such as s E. coli, and Salmonella sp. and Non-β-
lactamase-producing strains of H influenzae. The -amino
group is protonated in the gastric juice and acquires
electron withdrawing property and the molecule becomes
acid resistant. Also the -amino group creates new
asymmetric center; the D-isomer is eight times more active
than its L-isomer. Unfortunately these compounds are
sensitive to penicillinase and could be combined with -
lactamase inhibitors. Members of this class are ampicillin
and amoxycillin:
 Aminopenicillins
Ampicillin Bacteria thinks it is a nutrient as protein
It is D-(-)--Aminobenzylpenicillin. add polar group
H H
Ampicillin is administered orally as CH CO NH S Me

the trihydrate and parenterally as NH2

N Me
the soluble sodium salt. O
COOH
Formulations with sulbactam are
also available.
The existence of amino and carboxylic in the same molecule
renders the molecule amphoteric and forms Zwitterions that
its solubility becomes difficult in both acid and alkaline
media. Only 40 % of the dose of Ampicillin is absorbed orally
from the gut after oral administration. Esterification of the
carboxyl group of ampicillin to form prodrugs like
pivampiciilin and bacampicillin alters the polarity of the
molecule and improves oral bioavailability. The esters are
lipophilic compounds that are devoid of antibacterial activity
in their own right but are hydrolyzed by tissue esterases
during absorption to liberate ampicillin
Ampicillin Esters Used To Aid Absorption Through Gut Wall

Bacampicillin

Pivampicillin

double ester is essential because direct ester is highly stable and cannot be
broken down by esterases because it is bulky
Amoxicillin
It is D-(-)--Amino-p-hydroxybenzylpenicillin. It is
supplied as trihydrate for oral administration and as
sodium salt for parenteral use. A formulation with
clavulanic acid is also available. Amoxicillin has superior oral
absorption producing around 2.5 times the peak
concentration achieved by comparable doses of ampicillin.
The p-hydroxyl group adjusts the isoelectric point of the
drug to a more acidic value and is believed to be partially
responsible, along with the intestine dipeptide transporter,
for the enhanced blood levels obtained with amoxicillin
compared with ampicillin. Better oral absorption leads to
less disturbance of the normal GI flora and, therefore, less
drug-induced diarrhea.
H H
HO CH CO NH S Me
NH2
N Me
O
COOH
 acidic polar group has antipseumoal activity
2. Carboxypenicillins rather than amino group in ampicillin

Examples are Carbenicillin and ticarcillin

 They are broad-spectrum penicillins with
antipseudomonal activity
S
CH CO NH
CH CO NH
COOH
COOH
Carbenicillin, Ticarcillin,
-Carboxybenzylpenicillin -Carboxy-3-thienylpenicillin
(coadministered with clavulanic acid)
 The introduction of a polar group in their side chain
increases the activity against Gram -ve bacilli and
decreseas activity against Gram ve bacteria.
 They are not orally absorbed and are unstable
towards acids and -lactamases. So they should be
administered parenterally
3. Ureidopenicillins
e.g., Piperacillin
It is also parenteral broad-spectrum penicillin with
greater antipseudomonal activity than carboxypenicillins

piperacillin is usually coadministered

with tazobactam. The chemical
structure of piperacillin incorporates a
polar side chain that enhances
penetration into Gram-ve bacteria and
confers activity against the important
hospital pathogen Pseudomonas
aeruginosa.
d. Long Acting Penicillins
They are poorly absorbed after IM injection to slowly
liberate benzylpenicillin over a long period. They are
mainly used in the treatment of gonorrhea, syphilis,
and prophylaxis of rheumatic fever.
H H
+ +
CH2 N (CH2)2 N CH2 S
CH2 CONH
H H
N
O -
COO

Benzathine Penicillin is very slowly absorbed after IM

injection, yielding very low plasma concentration over a
period of 2-4 weeks
 ß-Lactamase Inhibitors
One of the problems associated with the use of
Penicillins is the rising threat of resistance,
which can occur by efflux pumping of the
antibiotic outside the bacterial cell or a change
in the structure of Penicillin binding proteins
(PBPs) to lower the binding ability of
Penicillins (such as the case with MRSA) or a
cell wall permeability problem But the most
common cause of resistance is the production
of ß-lactamases. so how can we combat this
dangerous enemy?
-LACTAMASE INHIBITORS show some weak
antibacterial activity, but have higher capacity
to inactivate many -lactamases. They are often
given in combination with penicillins to tackle
the problem of the resistance caused by the
presence of -lactamases from bacterial cell.
The -lactamase inhibitors in use are clavulanic
acid, sulbactam, tazobactam and avibactam.
These agents are given together with
hydrolyzable penicillins to protect them from
inactivation.
 i. Clavulanic Acid
An oxapenam that is available in combination
with Amoxicillin (Augmentin ®) or in
combination with Ticarcillin (Timentin ®).
H 4
6 5 O OH
3

N 2
1
O COOH
H
Clavulanic acid inhibits the -lactamase enzyme by
irreversible binding to the enzyme and allows the
amoxicillin to attack the peptidoglycan cell wall in order
to destroy the bacterial cell.
 Mechanism of action of Clavulanic acid

Amoxicillin/clavulanic acid is widely used to treat urinary, respiratory (upper:

tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, lower: bronchitis,
pneumonia), skin and dental infections
 ii. Sulbactam
It is coadministered with Ampicillin (Unasyn IM or IV)
or as the double esters of Ampicillin and Sulbactam
(sultamicillin, prodrug); Unasyn oral. A combination of
sulbactam with cefoperazone is also available.

O O
CH3
S
CH3
N
O COOH

sulbactam sultamicillin
 iii. Tazobactam
It is formulated with piperacillin. The combination is
mainly used intravenously in intensive care
medicine (pneumonia, peritonitis)

O O
CH3
S
N
CH2 N
N
N
O COONa
 iv. Avibactam
Non-β-lactam β-lactamase inhibitor available in
combination with ceftazidime approved by the FDA on
February 25, 2015, for treating complicated urinary tract
and complicated intra-abdominal infections caused
by antibiotic resistant-pathogens, including those caused
by multi-drug resistant gram-negative bacterial
pathogens.
 Mechanism of Action of β-Lactam antibiotics
 -lactam antibiotics inhibit bacterial cell wall synthesis by
inhibiting D-alanine transpeptidase (PBP) required for the
biosynthesis of peptidoglycan that is needed to provide
strength and rigidity to the cell wall.
 Bacterial cell wall structure
Gram-negative Bacterial Membrane Structure
Gram-negative bacteria are surrounded by two membranes.
The outer membrane functions as an efficient permeability barrier
containing lipopolysaccharides (LPS) and porins. it is
difficult for penicillin to invade Gram -ve bacterial cell wall because of
the fatty coating which acts as a barrier to polar, hydrophilic penicillin
molecule (-COO-). The only way in which penicillin can negotiate such
a barrier is through the hydrophilic porin channels in the outer
coating.
.

Cell Membrane

Peptidoglycan

Cytoplasmic Membrane
Gram –ve cell wall structure
Gram-positive Bacterial Membrane Structure
Gram-positive Membrane
The lipid bilayer cell membrane of most of the
Gram-positive bacteria is covered by a thick
peptidoglycan layer

Peptidoglycan Layers

Cytoplasmic Membrane
Gram ve
bacterial
cell wall
 Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
Resistance to β-Lactams – Gram pos.
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
Resistance to β-Lactams – Gram neg.
Scientists were then able to examine what
problems may limit Penicillins and improve on
them.
1) Spectrum: Why are older Penicillins inactive against
Gram negative bacteria?
a) Cell wall permeability. Solution: Add polar groups
b) Penicillinase activity, both an acylase and a ß-
lactamase. Solution: Add bulky groups as close as
possible to the ring, leading to a steric hindrance and
the enzyme is unable to break the ß-lactam.
2) Why are they acid labile? Solution: Add electron
withdrawing groups at the R-position.
3) Why do some organisms become resistant? Mainly
due to ß-lactamase production, that is enhanced by
mutations,induction and natural selection, and by a
change in cell wall permeability Solution: Similar to
Number 1.
 Structure Activity Relationship:
 1-position, if the sulfur is oxidized to the
sulfone/sulfoxide, it gives it better acid stability,
but becomes less active.
 2-position, any change will lower activity.
 3-position, the carboxylic acid is a must. If
changed to an alcohol/ester, it will be inactive.
 4-position, must have a nitrogen.
 5-position, no substitutions allowed.
 7-position, must have the carbonyl
Now the 6-position, specifically the R group,
 If add an electron withdrawing group, then
the amide oxygen will be less nucleophillic
and will thus give the compound better acid
stability.
 If a bulky group is added close to the ring,
then it makes the drug better resistant to ß-
lactamases, since it can not enter the active
site of the enzyme.
 If a polar group is added, its spectrum
becomes broader, since it can pass through
the hydrophilic porins in the Gram negative
bacteria cell walls.
 OMe Methicillin Amoxicillin
O H
H H H H H
H H C N
CH2
1
S CH3 HO CH CO NH S
N 5 S CH3 Me
6
C 2 NH2
N OMe N CH3 N
O O 4 CH3 O Me
3
COOH O
COOH COOH
Acid liability. Electron withdrawing group
Narrow spectrum Polar group Bulky group, β-Lactamse stable,, Orally active, Sensitive to ß-lactamases
Short duration Ester (benzathin penicilin) Acid sensitive
B-Lactamase sensitive Bulky group
-Methoxy group at C-6  steric hindrance
 high stability against -lactamases. Benzathin Penicillin
S
H H H
H H + +
CH CO N CH2 N (CH2)2 N CH2 S
S CH3 N CH2 CONH
O H H
NH2 N
N CH3 CH3 O -
O COO
COO CH Penam
Bacampicillin O COOEt 2
Long Acting Penicillins
prodrug orally active

Clavulanic Acid Sulbactam

H Oxacillin
4 O O R
6 5 O OH CH3 O H
3 S
C N S
N 2 CH3
1
O COOH R` N
H
N O CH3 N
O
O COOH COOH
oxapenam Orally active, ß-lactamases stable
ß-Lactamase Inhibitors
 Gram-positive and Gram-negative
Gram-positive bacteria are bacteria that give a
positive result in the Gram stain test. Gram-
positive bacteria take up the crystal violet stain
used in the test, and then appear to be purple-
coloured when seen through a microscope. This
is because the thick peptidoglycan layer in the
bacterial cell wall retains the stain after it is
washed away from the rest of the sample.

Gram-negative bacteria are a group

of bacteria that do not retain the crystal
violet stain used in the Gram staining method,
because their peptidoglycan layer is too thin to
retain the stain and is sandwiched between an
inner cytoplasmic cell membrane and
a bacterial outer membrane.
 Cephalosporins
 Cephalosporins are the second major group of
-lactam antibiotics to be discovered.
 Cephalosporins are similar to penicillins in
terms of mechanism of action, chemical
structure, and toxicities.
 Cephalosporin C, was the first member isolated
from Cephalosporium acremonium.

O
- S
OOC CH (CH2)3 C HN

NH3 N
+ O CH2OCOCH3

Cephalosporin C COOH
• The structure of cephalosporin C involves:
1. A six membered dihydrothiazine ring with an acetoxymethyl
group at its 3-position. This ring is fused to four membered -
lactam ring.
2. An -aminoadipoyl side chain at position 7.

• Properties of Cephalosporin C
1- Compared to Penicillin G, it is relatively more stable to acid
hydrolysis and more resistant to β-lactamase .
5. Cephalosporin C is not potent enough to be a useful
antibiotic, but removal of the C-7 side chain produces
7-aminocephalosporanic acid (7-ACA), which can be modified
to obtain the semisynthetic cephalosporins.

1
S O S H2N S
-
7 6
2 S Acylase
OOC CH (CH2)3 C HN
N
ONH 8
N
5
3
O N
N H 2O
CH OCOCH O CH2OCOCH3
3 4 2 3
+ O CH2OCOCH3
COOH COOH
COOH 7-ACA
 Stability of Cephalosporins
1 H S
R N S
H2N
-
OH or
O N C N
CH2OR -lactamase CH2OR
O O OH
COOH COOH
H2O Acylase Cephalosporoic acid
S
H2N
Fragments and
N
CH2OR rearrangement
O
products
COOH H+ /H2O O
7-ACA S
H+ H2O R` C N CH

S H C N
H2N CH2
HO O
N COOH
O CH2 Anhydrodesacetyl
C cephalosporoic acid
O H
O 1
N S
R
Desacetyl-7ACA
O N
lactone CH2OH
O
COOH
R = COCH3 = Acetyl
H
1
N S
R

O N
O CH2
C O
O
Desacetylcephalosporin
lactone
 Cephalosporins are named according to the following
skeletons
1
S S H2N S
7 6
2

N 3 N N
8 5 O CH2OCOCH3
O 4 O CH2OCOCH3

COOH COOH

3-Cephem Cephalosporanic acid 7-Aminocephalosporanic acid

(7-ACA)

General Formula of Cephalosporins

H
1
H
R N S

O N
O R2
COOH
 Classification of Cephalosporins
- They are classified into generations. This is not a
scientific classification, and is based on the time of
production of these drugs and their emergence in the
commercial market. But new products are usually
accompanied by a modification leading to some of the
desired and needed biological effects.
-First-generation cephalosporins are active predominantly
against Gram-positive bacteria, and successive
generations have increased activity against Gram-
negative bacteria with some reduced activity against
Gram-positive organisms.
- Fourth generation cephalosporins have a broad
spectrum activity against both Gram-negative and Gram-
positive organisms
First Generation Cephalosporins
 Produced between 1960-1970.
 Broad-spectrum activity against many
Gram-positive bacteria.
 They are not significantly active against
Gram-negative organisms.
 Poor ability to penetrate cerebrospinal fluid.
 Inactive against Pseudomonas.
 i. Cefadroxil 1
R = HO CH
2
R = CH3

NH2

ii. Cephradine 1
R = CH
2
R = CH3

NH2

iii. Cephalexine R1 = CH R2 = CH3

NH2

H
1
H
R N S

O N
O R2
COOH
Cephalexine General Formula for Cephalosporins

7-[(D--amino--phenyl)acetamido]-3-methyl-3- cephem-4-carboxylic acid.

 Second Generation Cephalosporins
 Produced between 1970-1980.
 Maintain gram positive coverage similar to first
generation agents.
 Increased activity against Gram-negative
organisms but still much lower toward Gram-
negative organisms than third generation agents.
 i. Cefuroxime

The oxime group increases the

stability against β-lactamases

ii. Cefaclor
Chlorine increases acid stability, so
given orally
 iii. Cefprozil
Taken orally
 Third Generation Cephalosporins
 Produced after1980.
 Excellent Broader spectrum against Gram-
negative organisms but less active than first gen.
cephalosporins on Gram-positive organisms. Retain
activity on Staph. and Strept.
 Some drugs like ceftazidime and cefoperazone
have high activity against Pseudomonas
aeruginosa.
 More resistant to -lactamases
 A. Parenteral agents
 i. Cefotaxime

The oxime group increases the stability

against β-lactamases produced by Gram –
ve bacteria. The aminothiaziole ring
increases binding affinity to PBP and
enhances antimicrobial activity.

 ii. Ceftriaxone
 iii. Ceftazidime
more pronounced β-
lactamase stability,
greater anti–
Pseudomonal activity

 iv. Cefoperazone
With anti–Pseudomonal
activity. Also sold as co-
formulation with
sulbactam.
B. Oral Agents

i. Cefixime

ii. Cefdinir
 Fourth Generation Cephalosporins
 They are recent drugs.
 Extended spectrum against Gram -ve and Gram
+ve organisms
 Much more resistant to -lactamases.
 High penetration into BBB
 Active against Pseudomonas.
 i. Cefepime
The quaternary N-methyl
pyrrolidine group at C-3 seems to
help penetration into the porin
channels of gram-negative
bacterial cell wall more readily
than earlier cephalosporins.

 ii. Cefpirome
Structure-Activity Relationship of Cephalosporins
1. Acylation of amino group of 7-ACA 
Different Cephalosporins.
2. Acetoxy group at position 3 is easily leaving
group in acid medium  inactive lactone ring.
3. 2-Cephem  inactive.
4. Removal of -COOH at C4  inactive.
5. Saturation of the double bond of cephem 
inactive.
6. A methoxy group at 7 -position  increase
in resistance against -lactamases as in cefoxitin.

Cefoxitin

2nd gen-cephalosporin
7. Replacement of S with O or CH2 of
cephem at position 1 No change in activity.
8. Substitution of acetoxy group at position
3 leads to:
a. Increase acid stability.
b. Broadening of the antibacterial activity.
c. Increase penetration  increase in
activity against resistant bacteria.
d. Decrease in allergenicity.
 OTHER -LACTAM ANTIBIOTICS
1. Monobactams
NH
O
Monobactams exhibit no useful activity
against Gram +ve organisms or
anaerobes because of poor binding to
PBPs. Their activity against Gram -ve
bacteria, including Ps. aeruginosa is due
to PBP3 in Gram-ve bacteria.
Aztreonam

S O
H CH 3
H 2N
N N
H
N N
O
O SO 3H
CH 3
HOOC
CH 3
 Aztreonam (Azactam) is a synthetic
monobactam antibiotic, having a monocyclic,
rather than a bicyclic nucleus.
 This agent inhibits synthesis of bacterial cell
wall by high-affinity binding to penicillin-
binding protein (PBP3 ) which is found
primarily in aerobic, Gram-negative microbes.
 Aztreonam (Azactam) is highly resistant to ß-
lactamases.
 2. Carbapenems
i. Thienamycin
 The terminal NH2 in the side chain is a nucleophile
which attacks -lactam ring and decreases stability.

OH
6 4 2
CH3 C 5 3 S
1
NH2
H
N
O 7 COOH
 ii. Imipenem
 It is N-Formimidoylthienamycin, the most
successful of a series of chemically stable
derivatives of thienamycin in which the primary
amino group is converted to a non nucleophilic
basic function. Imipenem is hydrolyzed by the
renal enzyme dehydropeptidase (DHP-1), so it is
protected by being coadministered with Cilastatin
which is an inhibitor for DHP-1.
OH
H
S
H3C N NH
N H
O COOH
Cilastatin Na

O
CH3
HOOC HN
CH3
H S
COONa
H2N
 iii. Meropenem
 The -methyl group at C4 confers increased
stability to hydrolysis by dehydropeptidase 1
enzyme, thereby eliminating the need for a
dehydropeptidase inhibitor in the dosing
regimen.
HO CH3
H CH3
CH 5 S CON
4
H3C 3
CH3
N N
1 2
O COOH
Imipenem and meropenem have very wide spectrum among
the ß-lactams, providing good coverage of gram-negative
rods, gram-positive bacteria, and anaerobes.
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