SAR Tetracyclines

MACROLIDES
THIS PPT IS CONTRIBUTED BY

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INTRODUCTION
:
Macrolide antibiotics are so
named as they possess a
macrocyclic lactone usually
having 12 to 17 atoms
SOURCE:
These are produced by
streptomyces species and the
products of actinomycetes
Common Structural
Features:
O
5 common
chemical
features they
are
i.
A macro cyclic
lactone,
usually having
12 to 17 atoms Erythromycin
ii. A ketone
group
H3C
CH3
OH
HO
H3C
H3C
CH3
HO
OH
H3C
CH3
CH3
O
CH3
O
O
CH3
H3C
CH3
OH
CH3
iii. One or two aminosugars linked

to the nucleus.
iv. A Neutral sugar linked either to
amino sugar or to lactone ring
v. The presence of the dimethyl
amino moiety on the sugar
residue, which explains the
basicity of these compounds
and consequently formation
salts.
SPECTRUM OF ACTIVITY:
active against most species of gram
They are generally (+) bacteria both
cocci and bacilli.
The antibacterial spectrum of activity
of the more potent macrolides
resembles that of pencillin.
They also exhibit useful effectiveness
against gram(-)cocci, specially
Neisseria Species
MECHANISM OF ACTION:
PHYSICAL PROPERTIES:
Occurs as crystalline powders.
Water insoluble molecules.
stable in aqueous solutions at or
below room temperature.
Unstable in acidic conditions and
forms internal cyclic ketal.
CHEMICAL PROPERTIES:
Macrolides are stable in
aqueous solutions at or below
room temperature.
Macrolides are unstable under
acidic conditions &undergo an
intramolecular reactions to
form an inactive cyclic ketone.
Chemical Instability Of
Macrolides:
H+
O
CH3
OH
H3C
CH3
OH
HO
H3 O
OH
12
H3C
CH3
O
H3C
6
S1
H3C
CH3
O
CH3
CH3
OH
12
S1
HO
CH3
H3C
H3C
O
CH3
S2
Erythromycin
S2
Erythromycin
6,9-hemiketal
-H3O+
CH3
CH3
H3C
H+
H3C
HO
O
H3C
12
H3O+
6
S1
O
O
CH3
S2
Anhydroerythromycin
6,9;9,12-spiroketal
CH3
H3C
CH3
O
CH3
OH
12
H3C
S1
O
CH3
CH3
H3C
HO
S2
8,9-Anhydroerythromycin
6,9-hemiketal
STRUCTURAL ACTIVITY
RELATIONSHIP
As macrolide are unstable in

acidic pH,a no. of strategies have
been utilised to improve the acidic
stability of erythromycin.
The addition of hydroxylamine to
the ketone to form oxime e.g.
roxithromycin
10
alteration of c-6 hydroxyl group:

nucleophilic functionality which
initiates erythromycin
degradation.
The azalides (azithromycin) are
semi-synthetic 15-membered
congeners in which a nitrogen
atom has been introduced to
expand a 14-membered
precursor- leads to an extended
spectrum of action.
11
PHARMACOKINETIC ASPECTS:
These are administered orally
Erythromycin can also be given
parenterally, through
intravenous injections.
These diffuse readily into most
tissues but do not cross the BBB
& poor penetration into synovial
fluid.
12
Therapeutic Agents Of Macrolides:

Erythromycin:
O
H3C
CH3
H3C
OH
HO
CH3
H3C
HO
CH3
OH
H3C
CH3
CH3
O
O
CH3
O
O
CH3
H3C
Erythromycin
CH3
OH
13
Source:
Isolated from streptomyces erythreus
Physical properties:
Yellow to white crystalline powder
Soluble in alcohol, slightly soluble in
water
Stable at neutral PH
Dosage forms:
Oral and topical dosage forms
Enteric coted and delayed realese
dosage forms
14
Drug interactions:
Anticoagulants
Benzodiazepines
Cyclosporine
Antihistaminic drugs
These agents potentiate the action of
erythromycin
Adverse effects:
Abdominalcramps
Epigastric distress
Jaundice
Transient deafness
15
USES:
It is used to treat
The upper part of the respiratory tract

infections,
Mycoplasma pneumonia
Gonorrhoea.
It is a good choice for penicillinsensitive cases
16
Therapeutic agents of erythromycin

Erythromycin ethylsuccinate
Prodrug with more lipophilicity- longer duration of
action
Erythromycin estolate
A lipid soluble,acid stable prodrug with better oral
absorption
Erythromycin gluceptate
A water-soluble salt of glucoheptanoic acid for
parentral dosage forms
Erythromycin lactobionate
Erythromycin salt meant for parentral usage
17
Clarithromycin
O
Clarithromycin
H3C
CH3
Semisynthetic derivative of erythromycin obtained by selective methylation at c-6 position:

6-Methyl ether of erythromycin
CH3
O
HO
CH3
CH3
H3C
OH
12
H3C
HO
H3C
1`
CH3
CH3
O
CH3
OH
1``
CH3
OH
Clarithromycin
CH3
18
Advantages:
Cannot undergo cyclic ketal
formation, so doesnt cause cramp in
GI.
Higher blood concentrations.
More lipophyl.
Lower doses with less intervals
USES: Effective against
Borrelia burgdorferi,
mycobacterium
aviumcomplex
19
Azithromycin
H3C
Nitrogen
containing 1512
membered
5
lactone ring
1
3
macrolides(azali
des)
1``
Stable under
acidic conditions,
Azithromycin
because it
doesnt form
20
cyclic ketal.
N
CH3
H3C
OH
HO
H3C
CH3
CH3
OH
H3 C
N
HO
O
1`
CH3
CH3
OCH3
CH3
OH
CH3
CH3
CH3
USES:
In the treatment of urogenital infections
caused by N. gonorrhoeae and
Chlamydia trachomatis.
Widely prescribed for the treatment of
respiratory tract infections.
More active against gram(-)bacteria.
21
ROXITHROMYCIN:
Semi-synthetic 14-membered
ring macrolide antibiotic in
which the erythronolide lactone
ring has been altered to prevent
inactivation in the milieu.
22
USES:
Active against both gram(+) &
gram(-)
Treatment of skin, dental and
genital infections
Treatment of upper and lower
respiratory tract infections.
23
REFERENCES:
S.N.Pandeya,Textbook of medicinal chemistry

Rama Rao Nadendla,Medicinal chemistry
Sri Ram, Medicinal chemistry
The Mechanism of Action of Macrolides, and
Lovmar and Mns Ehrenberg .
Keicho N, Kudoh S (2002). "Diffuse
panbronchiolitis: role of macrolides .
Lopez-Boado YS, Rubin BK (2008). "Macrolides
as immunomodulatory therapeutic agents.
Curr Opin Pharmacol.
24

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MACROLIDES

THIS PPT IS CONTRIBUTED BY

iii. One or two aminosugars linked

As macrolide are unstable in

alteration of c-6 hydroxyl group:

Therapeutic Agents Of Macrolides:

The upper part of the respiratory tract

Therapeutic agents of erythromycin

Semisynthetic derivative of erythromycin obtained by selective methylation at c-6 position:

S.N.Pandeya,Textbook of medicinal chemistry

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