Download Macrolide Antibiotics

Macrolide Antibiotics
Dr. Afshin Fassihi
Department of Medicinal Chemistry
MUI (Fall 1395)
1
Introduction
Macrolide antibiotics are produced by species of
Strptomyces.
In 1950 the first drug of this class was
isolated:Picromycin
In 1952 Erythromycin and Carbomycin were
introduced into clinic.
O
O
CH3
HO
HO
CH3
H3C
H3C
H3C
O
H3C
N
CH3
CH3
R1
OH
H3C
OH
CH3
CH3
O
O
O
CH3
CH3
O
OR2
CH3
CH3
Picromycin
N
H3C
O
O
O
CH3
CH3
HO
O
O
H3C
CH3
OH
O
Erythromycin
CH3
2
General Structure
They all contain three characteristic parts in the molecule:
1) A highly substituted macrocyclic lactone: Aglycone.
2) A ketone group on the aglycone ring (usually).
3) An amino desoxysugar, Glycon, Ketone group
and,
Aglycone
In some of the macrolides,
a neutral desoxysugar: Glycon
Glycons are glycosidically
desoxy
attached to the aglycone ring.
O
H3C
CH3
R1
OH
CH3
CH3
H3C
OH
N
HO
O
H3C
O
O
CH3
CH3
CH3
O
O
OR2
CH3
CH3
OH
O
CH3
Erythromycin
desoxy
Glycon
3
General Structure continued…
O
CH3
HO
H3 C
HO
CH3
H3C
N
CH3
O
H3C
O
O
O
CH3
CH3
Methymycin
The lactone ring usually has
12, 14, or 16 atoms.
This ring is sometimes
unsaturated with olefinic
bonds conjugated with the
ketone group.
H3C
O
O
O
H3C
CH3
R1
OH
H3C
CH3
CH3
OH
HO
H3C
O
CH3
O
CH2CHO
N
O
O
O
OR2
CH3
CH3
OH
O
Erythromycin
CH3
CH3
CH3
HO
H3CO
O
H 3C
N(CH3)2
O
O
O
O
O
H3C
O
O
CH3
O
O
CH3
Miocamycin
4
Having a dimethyl amino group on the glycon part:
Macrolide antibiotics are weak bases with
different salts of pKa 6.0-9.0.
As weak bases they are predominantly absorbed
in the alkaline intestinal environment.
O
H3C
CH3
R1
OH
H3C
CH3
CH3
OH
N
HO
H3C
O
CH3
O
O
O
CH3
CH3
O
OR2
CH3
CH3
OH
O
Erythromycin
CH3
5
General Structure continued…
Macrolides are water-insoluble lipophilic molecules.
Salts prepared by glucoheptonic acid
(glucoheptonate=gluceptate) and lactobionic acid
(lactobionate) are water soluble,
COOH
H
OH
H
OH
HO
H
H
OH
H
OH
COOH
CHO
H
HO
OH
H
HO
H
O
H
OH
H
O
OH
HO
H
CH2OH
H
OH
H
OH
CH2OH
CH2OH
CH2OH
Glucoheptonic acid
HO
OH
Lactobionic acid
Glucose
6
Stearic acid and laurylsulfuric acid salts are waterinsoluble.
OH
OH
Stearic acid, C18H38O2
O
O
S
O
Laurylsulforic acid C12H26SO4
OH
Macrolides are:
•
Stable in neutral aqueous solutions at room
temperature.
•
Unstable in acidic conditions or at high temperatures.
7
Mechanism of Antimicrobial Activity
 Macrolides attach to the rRNA adjacent to the peptidyl
transferase center in the 50s portion of bacterial
ribosomes and inhibit the protein synthesis.
 They block the enzymes that catalyse the transfer of
the new amino acid residue to the peptide chain, that
is, prevent elongation in prokaryotic cells.
8
9
Erythromycin bound to 16s rRNA, E. coli
10
Spectrum of Antibacterial Activity
Macrolides are similar to penicillins regarding their spectrum
of activity:
Macrolides are effective against most of the G(+) bacteria,
cocci or bacillus.
They are effective against penicillin-resistant strains.
They are less effective against G(-) bacteria, though some
strains of H. influenza and Brucella are sensitive to the
antibacterial activity of this class of antibiotics. G(-) cocci,
especially Neisseria Spp are also sensitive to macrolides.
In contrast to penicillins, macrolide antibiotics are effective
against Mycoplasma, Clamidia (G-), Campylobacter (G-) and
Legionella (G-).
11
Chemical Instability of Macrolide
Antibiotics
Macrolides are unstable under acidic conditions
and undergo an intramolecular reaction to form an
inactive cyclic ketal.
CH3
H3C
The important C12-OH for
binding to U2609 is gone
HO
The important C6-OH for
binding to A2062 is gone
8
9
CH3
O
H3C
O
12
CH3
N
6
HO
O
O
1
CH3
CH3
O
H3C
CH3
1`
3
O
O
OR2
CH3
1``
CH3
OH
O
Anhydroerythromycin
6,9;9,12-spiroketal
CH3
12
H+
O
CH3
OH
H3C
CH3
9
OH
HO
OH
12
6
5
H3C
O
O
1
CH3
H 3O +
O
H3C
12
6
S
H3C
1
O
O
1
CH3
3
O
O
CH3
CH3
OH
S1
3
O
8
9
HO
CH3
H3C
H
H3C
O
CH3
S2
Erythromycin
S2
Erythromycin
6,9-hemiketal
-H3O+
CH3
CH3
H3C
H+
H3C
HO
8
9
O
H3C
O
12
CH3
H 3O
6
1
3
O
O
CH3
1
CH3
S2
Anhydroerythromycin
6,9;9,12-spiroketal
CH3
6
OH
H3C
O
O
O
CH3
H3C
S1
H3C
O
12
+
8
9
HO
S1
O
3
O
O
CH3
S2
8,9-Anhydroerythromycin
6,9-hemiketal
13
Chemical Instability continued...
The cyclic ketal is the cause of intestinal cramp which
is reported after the use of erythromycin.
Water-insoluble salts and enteric coated dosage
forms of macrolides have less such a side effect.
Water insoluble forms cannot take part in the
reactions which occur in aqueous solutions.
Stearate and laurylsulfate salts are insoluble salts of
erythromycin.
14
Therapeutic Agents
Erythromycin
 It is isolated from Streptomyces erythraeus in 1952.
Erythronolide
Aglycone: Erythronolide,
Amino sugar: Desosamine,
Neutral sugar: Cladinose.
O
H3C
CH3
H3C
OH
HO
CH3
H3C
HO
N
CH3
OH
Desosamine
H3C
O
O
O
CH3
CH3
O
O
CH3
O
Cladinose
O
CH3
H3C
CH3
OH
Erythromycin A
15
O
Erythromycin
H3C
CH3
R1
OH
CH3
CH3
H3C
OH
N
HO
O
H3C
O
O
CH3
CH3
CH3
O
O
OR2
CH3
CH3
OH
O
CH3
Erythromycin A: R1=OH, R2=CH3
Erythromycin B: R1=H, R2=CH3
Erythromycin C: R1=OH, R2=H
Erythromycin D: R1=H, R2=H
16
Erythromycin
Erythromycin has been the subject of chemical
manipulations.
The chemical manipulations are:
1. Preparation of acidic salts such as glucoheptonate,
and stearate on the dimethyl amino group.
2. Ester formation on the 2`-OH of the amino sugar.
Ethylsuccinate and propionate are examples.
17
Erythromycin
These manipulations on erythromycin are
aimed to:
a) Increase the water solubility of the drug for
parenteral dosage forms:
• Hydrochloride, glucoheptonate and lactobionate
salts.
b) Increase the lipid solubility and hence chemical
stability of the drug against aqueous acidic
conditions as well as increase in oral absorption
and masking the bitter taste of the drug:
• stearate and laurylsulfate salts,
• ethylsuccinate and propionate esters.
18
O
Erythromycin
esters and salts
H3C
CH3
HO
OH
CH3
CH3
H3C
OH
RO
H3C
O
O
O
NH HA
CH3
CH3
CH3
O
O
OCH3
CH3
CH3
OH
O
CH3
Water Soluble:
Erythromycin Hydrochloride: R=H, Salt: HCl
Erythromycin Gluceptate: R=H, Salt: structure A
Erythromycin Lactobionate: R=H, Salt: structure B
A:
B:
COOH
COOH
H
OH
H
OH
HO
H
H
OH
H
OH
CH2OH
H
HO
OH
HO
H
H
O
H
OH
OH
O
OH
CH2OH
CH2OH
Water Insoluble:
Erythromycin Stearate: R=H, Salt: CH3(CH2)16CO2H
Erythromycin Ethylsuccinate: R=CO(CH2)2CO2C2H5
Erythromycin Estolat: R=COC2H5, Salt: CH3(CH2)11OSO3H
19
Clinical Application
of Erythromycin
It is used to treat
The lower and upper part of the respiratory tract
infections,
Soft tissue G(+) infections,
Mycoplasma pneumonia caused pneumonia,
Campylobacter jejuni enteritis,
Clamidia infections (G-).
Gonorrhoea (G-).
It is a good choice for penicillin-sensitive cases.
20
Clarithromycin
6-Methyl ether of erythromycin (semisynthetic), so:
cannot undergo cyclic ketal formation: no GI cramp.
More lipophylicity so:
• Higher blood concentrations.
• Longer intervals: every 12 hours
OH is important to
attach to A2062 by
hydrogen bonding
O
H3C
CH3
9
CH3
O
HO
Less active than erythromycin:
H C
Lacks a good binding site.
H C
250 and 500 mg EC tablets.
Its hepatic metabolism produces
the more active 6-OH analogue,
another reason for longer intervals.
CH3
CH3
OH
3
N
6
HO
3
CH3
O
O
O
CH3
O
H3C
O
OH
CH3
CH3
OH
O
Clarithromycin
CH3
21
Azithromycin
Azalide, a semisynthetic macrolide with a 15 membered ring.
Stable under acidic conditions, because it doesn’t form cyclic
ketal.
Longer half-life, due to the nitrogen atom
in the macrocyclic lactone ring,
longer intervals: every 24 hours.
H3C
The important C12-OH for
binding to U2609
Capable for necessary
interactions
The important C6-OH for
binding to A2062
N
CH3
H3C
OH
HO
12
H3C
OH
N
HO
5
H3C
In the treatment of urogenital
infections caused by:
N. gonorrhoeae and
Chlamidia trachomatis.
CH3
CH3
O
O
O
1
CH3
1`
CH3
CH3
3
O
O
CH3
OCH3
1``
CH3
OH
O
22
Azithromycin
CH3
Erythromycyclamine
Another semisynthetic derivative of erythromycin
with 9-amino instead of 9-keto group.
Lacks the GI cramp as a side effect.
The same antibacterial effects as erythromycin.
The important C12-OH for
binding to U2609
NH2
H3C
The important C6-OH for
binding to A2062
CH3
OH
HO
CH3
CH3
H3C
OH
N
HO
O
H3C
O
O
CH3
CH3
CH3
O
O
OCH3
CH3
O
Erythromycylamine
OH
23
Dirithromycin
A more lipophyl prodrug with high oral absorption.
For infections of the upper and lower parts of respiratory
system with only one daily oral dose.
O
HN
H3C
9
CH3
OH
HO
CH3
O
CH3
CH3
11
H3C
O
N
HO
O
H3C
O
O
CH3
CH3
CH3
O
O
OCH3
CH3
O
Dirithromycin
OH
CH3
24
Dirithromycin
Metabolism
Unstable 9N,11O oxazine ring is easily hydrolyzed to
yield erythromyclamine.
O
HN
H3C
9
NH2
H3C
OH
HO
CH3
OH
H3C
O
O
H3C
O
O
HO
CH3
O
H3C
CH3
O
O
Metabolism
CH3
CH3
OCH3
CH3
O
O
Dirithromycin
CH3
O
O
OCH3
CH3
CH3
O
O
N
N
HO
CH3
CH3
CH3
11
CH3
H3C
CH3
OH
HO
CH3
O
OH
OH
CH3
Erythromycylamine
25
Troleandomycin
Oleandomycin
Oleandomycin is isolated from Streptomyces antiboticus.
Troleandomycin is a prodrug of the former (acetyl of C2’-OH).
Lacks the GI cramp due to the lack of 6-OH.
The same antibacterial effects as erythromycin.
O
H3C
9
CH3
CH3
H3C
OH
N
6
HO
H3C
H3C
O
O
O
CH3
CH3
O
O
CH3
CH3
O
Oleandomycin, R=H
CH3
Troleandomycin R=COCH3
O
OR
26
Mechanism of Microbial Resistance
Methylation of a guanine residue on ribosomal RNA leads
to lower affinity toward macrolides.
Mutation of the Adenine 2058 in 23 rRNA causes a 10000
fold decrease in the attachment of the drug.
27
Mechanism of …continued
The macrolide producing microorganism uses the same
way to protect its rRNAs against this antibiotic.
Maybe the antibiotic producing microorganisms
are the source of R factors that cause
the microbial resistance
In some bacterial strains, an active efflux system is
responsible for the resistance against macrolides.
28