medicinal chemistry

2. Macro Olides
Lactone
ring
Large
Macrocyclic lactone
The word macrolides itself defines its
character

3. General information
• Macrolides belong to polyketide class of natural
products.
• Macrolides are macrocyclic lactone ring of 12 or more
carbon atoms. This class of compounds includes a
variety of bioactive agents, including antibiotics,
antifungal drugs, prokinetics, and immuno
suppressants.
• Generally 14-, 15-, and 16-membered macrolides are a
widely used family of antibiotics.
• Has excellent antimicrobial activity against gram-
positive aerobic cocci and atypical pathogens.
• These antibiotics are bacteriostatic in nature and act by
inhibiting protein synthesis of bacteria's

4. • 1950, Picromycin isolated from Streptomyces
venezulae.
• 1952, Erythromycin (Streptomyces erthyreus)
and Carbomycin.
• From soil bacteria's
•Spiramycin
•Josamycin
•Rosamicin
Clinically inferior
than Erythromycin
and its derivatives

5. Macrolides act as bacteriostatic at low doses by inhibiting
bacterial protein synthesis, if to be said in short these
class of antibiotics inhibits 50S ribosomal subunits of
bacterial ribosome and inhibit peptide chain elongation
which collectively inhibits protein synthesis.
And at higher doses they also act a bactericidal.
Before knowing how these antibiotics acts against bacterias
we should know few things about eukarytoic and
prokaryotic ribosomes.
• Ribosomes are hetero cell organelles ( i.e., they have two
dissimilar structures) which is composed of RNA and
proteins (RIBONUCLEOPROTEINS).
• Ribosomes with regardless of type of organism it is of
two types i.e., cytoplasmic ribosomes and organellar
ribosomes.
• Ribosomes can again be classified into two types based
on the type of organism i.e., prokaryotic and eukaryotic
ribosomes.

7. MECHANISM OFACTION MACROLIDES
Macrolides are the inhibitors of 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.

8. Uses
• Upper respiratory infections:
Streptococcal pharyngitis,
tonsillitis, sore throat,
whooping cough
• Lower respiratory infections:
pneumonia, anthrax
• COPD

9. • Sinusitis
• Otitis media
• Peptic ulcer treatment for
eradication of H.pylori in
triple therapy
• Skin and soft skin infection
• MAC (Mycobacterium avium
complex) infection in AIDS
• Gonorrhoea
• Conjunctivitis
• Lyme disease

10. Other antibiotics acting by same
mechanism are:
• Lincosamides : ex: clindamycin and
lincomycin
• Oxazolidinones : ex: linezolid and tedizolid
• Streptogramins: ex: daflopristin and
quinapristin
• Glycopeptides : ex: vancomycin and
teicoplanin
• Chloramphenicol

11. Clinically used macrolides
Erythromycin Clarithromycin

12. Azithromycin Oleandromycin

13. The macrolides general structure contain three
characteristics parts in the molecule
• Lactone ring: large non-planar, strainless, 12-16
carbon ring.
• Ketone group: C-1 and C-9
• Glycosidically linked deoxy sugars:
*2 deoxy sugars
a) one is having substitued amino group
(mostly dimethyl amino group)
b) another is neutral sugar
* where D-Desoamine is the amino sugar and
L-Cladinose is the neutral sugar

15. • L-Cladinose
2,3,6-trideoxy-3-methoxy-3-methyl-L-ribohexose
•Where L-cladinose is derived from L-ribohexose
•The hydroxyl groups in 2,3,6 in L-ribohexose are
replaced by methoxy group at C3 and methyl
group at C3

16. • D-Disoamine
3,4,6-trideoxy-3-dimethylamino-D-xylohexose
•D-disosamine is derived from D-xylohexose (
where D-xylohexose is derived frome D-xylose
which is an epimer of ribose.

17. Epimers

18. CLASSIFICATION OF MACROLIDES
14-membered ring
• Natural: Erythromycin
• Semisynthetic: Roxithromycin, Clarithromycin
15-membered ring: Azithromycin
16-membered ring:
• Natural: Spirimycin, Josamycin
• Semi synthetic: Miokamycin, Rotikamycin

19. Special group macrolides:
• Azilides : Azithromycin (15) [lactone ring +
methylated nitrogen
• Triamilides: Tulathromycin (13, 15)
• Ketolides :
Telithromycin
Cethromycin
Solithromycin
Erythromycin derivatives
(cladinose + keto group
Lactone + cyclic carbamate group)

20. Erythromycin
• Saccharopolyspora erythrea – 1952
(Streptomyces erythreus)
• Erythromycin is generally available in 4 forms
R1 R2
A -OH -CH3
B -H -OCH3
C -OH -OH
D -H -OH
(L-Mycarose)

21. Erythromycin A

22. Easy way to remember the structure of
erythromycin
Remember the position of functional groups
• Even places : 2,4,6,8,10,12 ⑥ -CH3
• 1,9 : ketone
• 6, 11, 12: hydroxyl group
• 13: Ethyl group
• 14: lactone oxygen

23. • Erythromycin is very bitter in taste hence to
overcome the bitterness, irregular oral
administration it is available in enteric coated
and delayed release dosage forms.
• Acid degradation of erythromycin:
Erythromycin is unstable in acidic media, due to
formation of hemiketal inttermediate at C-9 by
reversible attack of C-6. Which again reacts with
C-12 forming spiroketal this results in cleavage of
cladinose from parent moiety and release of
desosamine.
The hemiketal inttermediates formed causes GI
cramping.

25. Ways to prevent acid degradation
In erythromycin C-6-OH is responsible for
internal ketal formation, hence inorder to
prevent this;
• Replace C-6-OH by –OCH3 {ex:clarithromycin}
• Increase the ring size up to 16 member
{ex:azithromycin}
• Enteric coated tablets
• Modified derivatives of erythromycin

26. Modified derivatives of erythromycin
In erythromycin, dimethyl amino group of desosamine
forms salts with acids, acidic salts would help in
prevent acid degradation of erythromycin. Acids that
can be used includes:
• D-glycero-D-glucoheptanoic acid :Erythromycin on
reacting with D-glycero-D-glucoheptanoic acid forms
Glucoheptonate salt also called as glucephate.
used IV- for legionnariers disease
• Lactobionic acid: Erythromycin on reacting with
Lactobionic acid forms Lactobionate salt which is
generally administered IV
• Stearic acid: Erythromycin on reacting with stearic acid
forms Stearate salt

27. In order to prevent acid degradation
erythromycin can be formed to Esters by
approaching 2-OH group of desosamine)
Ex: Ethyl succinate and propionate
• Stearate, Ethyl succinate and propionate salts
are available orally.
Available as Lauryl sulphate salt
called as Estolate

30. Macrolides are used to treat viral
conditions
• Lysosomotropic activity: Macrolides acccumaltes
within lysosomes and increases their pH causing
disruption of lysosomal membrane, which inhibits
viral replication. (viral replication is occurs in
phagolysosomal complex)
• Induction and accumulation of cholesterol,
phospholipids and other neutral lipids within
lysosomes causes dysfunction of lysosomes.
• Inhibition of lysosomal protease, which is a key
mediator in viral replication.
• Blocks interaction between virus and ACE2
receptors.

32. • M reduce virulence by inhibiting quorum sensing
and biofilm formation, and also facilitates initial
host defence by reducing the quantity and
consistency of sputum.
• After invasion, immune response is facilitated
when PAMP’s are recognised by TLR expressed
on immune cells and also M enhance
phagocytosis and subsequent intracellular killing
of virus by monocytic cells.
• M inhibit the release of pro-inflammatory
cytokines and chemokines, which impairs
recruitment of other immune cells to the lungs.

33. • Although M stimulate neutrophil degranulation,
the overall number of antimicrobial peptides
(such as myeloperoxidase and elastin) in the
lungs is lower after M treatment, presumably
because of reduced neutrophil influx.
• To resolve immune responses, effector cells
undergo apoptosis and specialised cells mediate
for tissue repair. M stimulate apoptosis of
neutrophils.
• M also disort the differentiation of monocytic
cells towards a tolerogenic (M2-like) phenotype.
Timely apoptosis and efferocytosis diminish the
release of DAMPs due to immunogenic cell death,
and therefore prevent the progression of
inflammation