Approved by PHARMACY COUNCIL OF INDIA – New delhi

Affiliated to THE TAMILNADU DR MGR MEDICAL UNIVERSITY - Chennai

ARUNAI COLLEGE OF PHARMACY - Tiruvannamalai

Prepared & Lecture by

Unit 1 - ANTIBIOTIC Part 5 – MACROLIDE’S Mr. Murugan
(Associate professor)

MEDICINAL CHEMISTRY-III (BP-601T) - B Pharmacy - VI Sem

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)

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

 Macrolides belong to polyketide class of natural products, O Aglycone

H3C CH3
 structurally contains macrocyclic lactone ring of 12 to 17 carbon atoms. 9
R1 OH CH3
 Generally 14, 15, and 16-membered are a widely used family of antibiotics. CH3
H3C OH N
12
HO CH3
5 O
 The macrolide’s general structure contain three characteristics parts H3C
O CH3
O 1`
 Aglycone moiety – macrocyclic Lactone ring: 12-16 carbon ring.
CH3 1 3
 Ketone group: C-1 and C-9 O
O
OR2 Glycon
 Two deoxy sugars linked Glycosidically to aglycone: CH3 1``
 amino sugar - D-Desoamine CH3
O OH
 neutral sugar - L-Cladinose
CH3
 position of functional groups Erythromycin

 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.

 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).

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.
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 Gram negative Aerobes: Azithro>Clarithro>Erythro

Erythromycin & Clarithromycin display best activity Newer macrolides - Azithromycin has enhanced activity.

Example: Stayphyloccous aureus Example: H. influenzae

Streptococcus pneumoniae Neisseria sp.

Corynebacterium sp. Bordetella pertussis

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