This document discusses macrolide antibiotics, including their mechanism of action, chemistry, classification, and optimization. Macrolides are a class of antibiotics that contain a macrocyclic lactone ring attached to deoxy sugars. They are bacteriostatic and inhibit bacterial protein synthesis by binding reversibly to the 50S subunit of ribosomes. Examples discussed include erythromycin, clarithromycin, and roxithromycin. Strategies to optimize macrolides focused on improving acid stability, such as modifying the C6 hydroxyl group or adding oxime groups.

1. Submitted by
Saurabh Gupta
21301148
M. Pharma 1st Semester
Submitted to
DR. Om Silakari Sir
Department of Pharmaceutical Sciences and Drug Research
Punjabi University, Patiala
Lead Optimization Of Macrolide Drug

2. Content
• Introduction
• MOA of Antibiotic
• Macrolides- General Consideration
• Mechanism of Action of Macrolide Antibiotics
• Inhibition Of Protein Synthesis
• Chemistry of Macrolides
• Classification of Macrolide Antibiotics
• Structure Activity Relationship
• Lead Optimization
• Structure of Macrolide Drug
• Roxithromycin
• Erythromycin
• Macrolide Indications

3. Antibiotics (From ancient Greek Antiviotika) also called
antibacterials, are a type of antimicrobial drug used in the
treatment and prevention of bacterial infections. They may either
kill or inhibit the growth of bacteria. Antibiotics are mainly
obtained from natural sources.
ANTIBIOTICS

5.  Macrolides are a class of antibiotics which contain macrocyclic
lactone ring attached to deoxy sugar.
 These antibiotics are bacteriostatic in nature & act by inhibiting
protein synthesis of bacteria.
 They prevent peptidyl transferase from adding the growin
peptide attached to tRNA to the next amino acid. They bind
reversibly to the P site of the 50s subunit of the ribosomes.
 These are obtained mainly from certain actinomycetes genus,
such as streptomyces.
 Example:- Erythromycin, Clarithromycin, Azithromycin,
Telithromycin etc.
Macrolides- General Consideration

6. • Macrolide is a protein synthesis inhibitor
Macrolide bind to 50S
ribosomal sub-unit
Inhibit polypeptide chain
elongation & protein
synthesis inhibiton
Result in inhibition of
growth & multiplication.
• Generally it is bacteriostatic in action but
acts as bacteriocidal at higher dose.
Mechanism of Action of Macrolide Antibiotics

7. Clarithromycin
binds to 50S r-RNA and inhibit
formation of peptide bond
Erythromycin
Binds to 50S r-RNA and prevents
movement along m-RNA
Azithromycin
Interfers with t-RNA anticodon
reading of m-RNA codon
Roxithromycin
Changes shape of 30S r-RNA and
causes m-RNA to be read
incorrectly
Inhibition Of Protein Synthesis

8. Macrolides structurally contain three
characteristic parts in every molecule
 A macrocyclic lactone ring containing
14 or 16 carbons usually.
 Multiple ketone group (O=) &
hydroxyl group (-OH).
 Two deoxy sugars attached by
glycosidic bond with lactone ring.
Chemistry of Macrolides

9. Macrolide
Antibiotics
14-
Membered
ring
Natural
Erythromycin
Oleandomycin
Semi synthetic
Roxithromycin
Clarithromycin
15-
Membered
ring
Semi synthetic
Azithromycin
16-
Membered
ring
Natural
Josamycin
Spiramycin
Midecamycin
Semi-synthetic
Miokamycin
Rokitamycin
Classification of Macrolide Antibiotics

10. Structure Activity Relationship
 A lactone ring, ketonic group and an
amino sugar are the basic
characteristic groups that are desired
for activity.
 Amino sugar must be glycosidically
bonded
 Dimethyl amino group provides basic
properties to macrolides.
 Lactone ring contain 12, 14, 16 atoms
in cyclic ring along with olephinic
group.

11. Structure Activity Relationship
 C-2 F is more active and less toxic & enhance Pharmacokinetic
Properties.
 C-6 OH- group replaced by OCH3 , Clarithromycin → Acid Stable.
 C-8 methyl group replaced by F, Flurithromycin →Acid Stable
 C-9 , Formation of Oxime (=NOH) / Hydrazine (=NNH2) →
Increased Lipophilicity activity & toxicity → Roxithromycin (-
CH2OC2H2OCH3)
 C-9 , Formation of azilide → No GI cramping , Better
Pharmacokinetic properties → Azithromycin.
 C-11, 12, Cyclic Carbonate/ Carbamate → Increased Potency & acid
stability
In Cladinose
 C-3’ Introduction of F less Activity
 C-4’, OH – Replaced by NH2 active against gram negative bacteria.
In desosamine
 C-3”, dimethyl amino group → Important → Acid Salts → Acid
stable.
 C-2” , OH- group are important ester → acid stable.

12. Lead Optimization
Conversion to amines
Conversion to oxime
Ring Expansion
Conversion to 11, 12-
cyclic derivatives
Replacement of hydrogen Alkylation of hydroxyl group
Cut Cladinose to ketolides

13. Lead Optimization
 Alkylation at C-6 provides acidic stability.
 Ring expansion is done by Beckmann rearrangement and is effective against
erythromycin a resistance strain.
Ketolides
 Semisynthetic derivatives of erythromycin A
 Highly stable in acidic environment.
 Overcome erythromycin A resistance.
 Unable to induce MLSB resistance (Macrolide-lincosamide-streptogramin
B)
Specific Features
 3-Keto Function (Lack L-Cladinose)
 Side Chain C11-C12

14. • A number of strategies have been utilized to improve the acid stability of
erythromycin.
• The first approach involved the addition of hydroxylamine to the ketone to
form oxime – e.g., Roxithromycin.
• The second approach involves an alteration of C-6 hydroxyl group, which is
the nucleophilic functionality that initiates erythromycin degradation.
Modification that removes the nucleophilic nature of this hydroxyl group
can retain antibacterial properties if the size of kept small so as not to affect
the ribosomal binding- e.g. Clarithromycin
• The azalides (E.g. azithromycin) are semi- synthetic 15-membered
congeners in which a nitrogen atom has been introduced to expand a 14-
numbered precursor, and this leads to an extended spectrum of action.
Lead Optimization

15. Macrolide Drug X R
Erythromycin O H
Roxithromycin NOCH2O(CH2)2OCH3 H
Clarithromycin O CH3
Structure of Macrolide Drug

16. Biological source:- Clarithromycin, a
semisynthetic macrolide antibiotic derived from
erythromycin
Mechanism of Action:- Clarithromycin is first
metabolized to 14-OH clarithromycin, which is active
and works synergistically with its parent compound.
Like other macrolides, it then penetrates bacteria cell
wall and reversibly binds to domain V of the 23S
ribosomal RNA of the 50S subunit of the bacterial
ribosome, blocking translocation of aminoacyl
transferase RNA and polypeptide synthesis.
Clarithromycin also inhibits the hepatic microsomal
CYP3A4 isoenzyme and P-glycoprotein, an energy-
dependent drug efflux pump.
Clarithromycin

17. • Biological source:- Roxithromycin
is a semi-synthetic derivative of the
macrolide antibiotic erythromycin
that includes an N-oxime side chain
on the lactone ring with antibacterial
and anti- malarial activities.
• Mechanism of Action:-
Roxithromycin prevents bacterial
growth by interfering with their
protein synthesis. It binds to the 50S
subunit of bacterial ribosomes and
inhibits the translocation of peptides.
Roxithromycin

18.  Upper respiratory tract infections- pharyngitis, tonsillitis, sore throat,
whooping cough etc.
 Lower respiratory tract infections- pneumonia, mycoplasma,
pneumonia, community derived pneumonia, anthrax etc.
 COPD
 Sinusitis
 Peptic ulcer treatment for eradication of H. pylori in triple therapy.
 Skin & soft tissue infection
 MAC (Mycobacterium avium complex) infections in AIDS
 Gonorrhea
 Conjunctivitis
 Lyme disease
Macrolide Indications