Macrolide antibiotics

Lead optimization of macrolide antibiotics

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

2. Contents 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 20 th 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 1 st Erythromycin Oleandomycin Spiramycin 2 nd Roxithromycin Clarithromycin Azithromycin Dirithromycin 3 rd 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

10. 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

11. 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

12. 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

13. 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.

14. Lead Optimisation

15. Lead Optimisation Alkylation at C-6 provides acidic stability Ring expansion is done by Beckmann rearrangement and is effective against Erythromycin A resistant strains

16. 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

17. 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.

18. 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.

19. Thank You