The document provides an overview of macrolide antibiotics, detailing their historical development, chemical structure, and classification. Key macrolides like erythromycin, clarithromycin, and azithromycin are discussed in terms of their mechanism of action, therapeutic uses, and side effects. It also covers the evolution of these antibiotics and their clinical applications, highlighting their effectiveness against various bacterial infections.

1. MEDICINAL CHEMISTRY-III (BP-601T) - B Pharmacy - VI Sem
ARUNAI COLLEGE OF PHARMACY - Tiruvannamalai
Unit 1 - ANTIBIOTIC Part 5 – MACROLIDE’S
Approved by PHARMACY COUNCIL OF INDIA – New delhi
Affiliated to THE TAMILNADU DR MGR MEDICAL UNIVERSITY - Chennai
Prepared & Lecture by
Mr. Murugan
(Associate professor)

2. Syllabus:
Historical background, Nomenclature, Stereochemistry, Structure activity relationship, Chemical
degradation classification and important products of the following classes.
Macrolide: Erythromycin Clarithromycin, Azithromycin
Pervious The Tamilnadu Dr MGR Medical university exam question
Mar 2021 Write a note on Macrolide antibiotics (5 mark)
Mar 2021 Mechanism action of Erythromycin (2 mark)
Oct 2022 Classify macrolides with examples (2 mark)
Aug 2023 Give the structure and uses of: a) Tetracycline b) Erythromycin (5 mark)
Dec 2023 Structure and uses of Azithromycin and Clindamycin (5 mark)
Dec 2023 Mechanism action of Clarithromycin (2 mark)

3. History:
 antibiotics isolated from actinomycetes is the group of chemically related compounds called the macrolides.
 1950, picromycin, the first of this group to be identified as a macrolide compound,
 1952, erythromycin and carbomycin were reported as new antibiotics,
 1970 – 1980 semisynthetic derivatives of macrolide was developed
 Currently, more than 40 such compounds are identified
 erythromycin and semisynthetic derivatives of erythromycin (e.g., clarithromycin and azithromycin), which
have superior pharmacokinetic properties, enhanced acid stability and improved distribution properties
Definition:
Macrolide are a group of broad-spectrum antibiotics, produced by various strains of streptomyces and
having a macrolide ring structure linked to one or more sugar moiety. Which inhibit the protein synthesis
to produce bacteriostatic activity.
Example: Erythromycin, Clarithromycin and Azithromycin

4.  Macrolides belong to polyketide class of natural products,
 structurally contains macrocyclic lactone ring of 12 to 17 carbon atoms.
 Generally 14, 15, and 16-membered are a widely used family of antibiotics.
 The macrolide’s general structure contain three characteristics parts
 Aglycone moiety – macrocyclic Lactone ring: 12-16 carbon ring.
 Ketone group: C-1 and C-9
 Two deoxy sugars linked Glycosidically to aglycone:
 amino sugar - D-Desoamine
 neutral sugar - L-Cladinose
 position of functional groups
 Methyl group - Even places : 2,4,6,8,10,12 = ⑥
 Keto group - 1,9
 Hydroxy group - 6, 11, 12
 Ethyl group - 13
 Lactone oxygen -14
macrolide are weak bases and different salts with pKa range of 6.0-9.0
 Macrolides are stable in aqueous solutions at or below room temperature.
 They are unstable in acidic or basic conditions or at high temperatures.
O
O
O
CH3
R1
H3C
CH3
CH3
O
H3C
OH
H3C
CH3
OH
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OR2
1 3
5
9
12
1`
1``
Erythromycin
Glycon
Aglycone

7.  C6 hydroxy group in erythromycin has been converted to an methoxy, Greater acid stability, Higher blood
concentrations. More lipophilicity, Longer half-life but less active. E,g clarithromycin
 The addition of hydroxylamine to the ketone to form oxime. Increased acid stability. E.g Rox
 Nitrogen atom has been introduced to expand a 14- membered ring to 15-membered azalide ring. Removal
of the 9-keto group coupled with incorporation of a weakly basic tertiary amine nitrogen function into the
macrolide ring increases the stability. E.g azithromycin.

 C-11 carbamate side chain increases affinity for the ribosomes, e.g., Lankamycin.
 Addition of C-2 fluoro group (-F) enhanced activity against both susceptible and resistant organisms and
imroved pharmacokinetics. E.g. Fluorithromycin
 L-Cladinose moiety at C-3 can be successfully replaced with a keto group resulting in improved activity,
e.g., ketolides (e.g., Telithromycin).

9. Macrolides are inhibiting protein synthesis (interferes with translocation). They binds reversibly to the ‘P-site’
of 50s subunit of ribosome. It prevents the peptidyl transferase from adding the peptide to the growing chain
attached to t-RNA. They are bacteriostatic or bactericidal depending on the concentration of drug at the site.

10. Erythromycin is a naturally-occurring macrolide derived from Streptomyces erythreus – problems with
acid lability,
narrow spectrum,
poor GI intolerance,
short half-life.
Structural derivatives include clarithromycin and azithromycin, roxithromycin (Newer macrolides)-
Broader spectrum of activity ,
better bioavailability,
better tissue penetration,
prolonged half-lives
Gram Positive Aerobes: Clarithro>Erythro>Azithro
Erythromycin & Clarithromycin display best activity
Example: Stayphyloccous aureus
Streptococcus pneumoniae
Corynebacterium sp.
Gram negative Aerobes: Azithro>Clarithro>Erythro
Newer macrolides - Azithromycin has enhanced activity.
Example: H. influenzae
Neisseria sp.
Bordetella pertussis

11. Therapeutic uses
 Skin & soft tissue infection
 Whooping cough
 Sinusitis, Pharyngitis, Tonsillitis
 Pneumonia
 Respiratory tract infection
 Eradication of H.Pylori
 Diphtheria
 Gonorrhoea & Syphilis
 Typhoid & malaria
Adverse effects
 Headache, Dizziness
 Taste disturbances
 Stomatitis, Mild gastric upset, Abdominal pain
 Hepatitis, Jaundice
 Hearing problem