2. • Introduction & History
•Macrolide Antibiotics
• Classification
•Structures
•Chemistry
•Mechanism of action
• Structure Activity Relationship
• Lead Optimization
3. Introduction & History
Antibiotic (from ancient Greek antibiotika) also called
antibacterial, is a type of antimicrobial drug used in
the treatment and prevention of bacterial infections.
Before the 20th century, treatments for infections were
based primarily on medicinal folklore. Many ancient
cultures, including the Egyptians and Greeks used
mold and plant materials and extracts to treat
infections
4. Macrolide Antibiotics
Macrolide antibiotics belong to the family of
macrocyclic antibiotics
Macrolide means large macrocyclic lactone and was
first used by R. B. Woodward for the class of natural
products produced by Streptomyces species.
These are generally lipophilic and consist of a central
highly substituted lactone ring.
9. Chemistry
Characterstic features of
macrolides are:
Large lactone ring
Ketone group
Glycosidically linked
amino sugar
May have a neutral sugar
too
Bases that form salts of
pka 6-9
10.
11. Structure Activity Relationship
A lactone ring, ketonic
group and an amino sugar
are the basic characteristic
groups that are desried for
activity.
Amino sugar must be
glycosidically bonded
Dimethyl amino group
provides basic properties
to macrolides
Lactone ring contains 12,
14, 16 atoms in cyclic ring
along with olephinic group
12. SAR Contd…
Reduction at C-9 results in more stable product but is
less potent
Modification at C-8 leads to the acidic stability
11, 12 – carbonate were prepared which were more
stable and had double activity but had hepatotoxic
potential
13. SAR Contd…
Removal of hydroxyl
group at C-6 leads to
decrease in potency
11, 12 – methylene cyclic
acetals were found to be
more active than parent
compound in vitro
14. SAR Contd…
3’’ epimerization of
cladinose indicated that
stereochemistry at 3
position is not important
for the antibacterial
activity.
Increasing the number
of atoms in the core
skeleton lead to greater
acidic stability and
improved bioavailability.
16. Lead Optimisation
Alkylation at C-6 provides acidic stability
Ring expansion is done by Beckmann rearrangement
and is effective against Erythromycin A resistant
strains
17. Ketolides
Semisynthetic drivatives of erythromycin A
Highly stable in acidic environment
Overcome Erythromycin A resistance
Unable to induce MLSB resistance
Specific features :
3-keto function (Lack L-Cladinose)
Side chain C11 – C12
18. Telrithromycin
Telrithromycin is the
first ketolide (3-keto
macrolide derivatives)
It is prepared by
removing the cladinose
sugar from the C-3
position of the
erythronolide skeleton
and oxidising the
remaining hydroxyl
group to keto group.
19. Telrithromycin Contd…
In addition to the C-3 ketone, telrithromycin has an
aromatic N- substituted carbamate extension at
position C-11 and C-12. This ring has an imidazo-
pyridyl group attachment.
Telrithromycin possesses a 6-OCH3 group (like
clarithromycin), avoiding internal kemiketalization
with the 3- keto function and giving the ketolide
molecule excellent acidic stability.
The ketolides are very active against respiratory
pathogens, including erythromycin- resistant strains.