medicinal chemistry of MACROLIDES / Erythromycin / Clarithromycin / Azithromycin

1. Organic Medicinal and
Pharmaceutical
Chemistry
Mustafa K. Zuhdi

2. MACROLIDES
Hestory : Among the many antibiotics isolated from the
actinomycetes is the group of chemically related
compounds called the macrolides.
In 1950, picromycin, the first of this group to be identified
as a macrolide compound, was first reported.
In 1952, erythromycin and carbomycin were reported as
new antibiotics, and they were followed in subsequent
years by other macrolides.

3. Chemistry
The macrolide antibiotics have three common chemical
characteristics:
1) a large lactone ring (which prompted the name
macrolide).
2) a ketone group .
3) a glycosidically linked amino sugar.
Usually, the lactone ring has 12,14, or 16 atoms in it, and
it is often unsaturated, with an olefinic group conjugated
with the ketone function. such as natamycin

4. MACROLIDES
picromycin

5. Mechanism of Action
Macrolide bind to 50S ribosomal
subunit
Inhibit polypeptide chain elongation &
protein synthesis inhibition
Result in inhibition of growth &
multiplication

6. Uses
 Streptococcal pharyngitis
 Tonsillitis
 Respiratory infection
Diphtheria
 Tetanus
 Syphilis & gonorrhea

7. Erythromycin
 is soluble in alcohol and in the other common organic
solvents but only slightly soluble in water.
 pKa of 8.8 .
 pH in the range of 8.0 to 10.5 .
 Erythromycin has been chemically modified with
primarily two different goals in mind
i. to increase either its water or its lipid solubility for
parenteral dosage forms
ii. to increase its acid stability for improved oral
absorption.

8. Erythromycin

9. Erythromycin

10. (Biaxin)
Clarithromycin
is the 6-methyl ether of erythromycin.
The simple methylation of the 6-hydroxyl group of
erythromycin creates a semisynthetic derivative that fully
retains the antibacterial properties of the parent antibiotic.
Clarithromycin, like erythromycin, inhibits cytochrome
CYP3A4 oxidases and, thus, can potentiate the actions of
drugs metabolized by these enzymes.

11. Clarithromycin

12. (Zithromax)
Azithromycin
 is a semisynthetic derivative of erythromycin .
 prepared by Beckman rearrangement of the
corresponding 6-oxime, followed by N-methylation
and reduction of the resulting ring-expanded lactam.
 Removal of the 9-keto group coupled with
incorporation of a weakly basic tertiary amine
nitrogen function into the macrolide ring increases the
stability of azithromycin to acid-catalyzed degradation.
 Azithromycin is not metabolized to any significant
extent.

13. Azithromycin

14. References
Wilson and Gisvold's Textbook of Organic Medicinal and
Pharmaceutical Chemistry, 12th Edition .