Lead optimization of macrolide antibiotics

1. Macrolide Antibiotics
 Submitted to:-
Dr. Om Silakari
 Submitted by:-
Lakshay Gupta

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.

5. Classification

6. Structures

7. Three waves of macrolides
Waves
 1st Erythromycin
Oleandomycin
Spiramycin
 2nd Roxithromycin
Clarithromycin
Azithromycin
Dirithromycin
 3rd Ketolides
Objectives
 S. aureus peni- R
 Atypical microorganisms
 Improvement of
pharmacokinetics
 Overcome resistance to
erythromycin A
 Enhance activity against
Gram positive bacteria

8. Unstability in acidic media

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

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.

15. Lead Optimisation

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.

20. Thank You