Download Wilson and Gisvold` s Textbook of Organic Medicinal and

Wilson and Gisvold’ s Textbook of Organic Medicinal and Pharmaceutical Chemistry
Chapter 8 Page 308
Macrolides
They are antibiotics produced by Streptomyces
species
Chemistry
They contain macrocyclic lactone ring (highly
substituted monocyclic lactone named aglycone),
to which; one or more deoxy sugars, usually
cladinose (neutral sugar) and desosamine
(amino sugar ) are attached at 3 & 5, and a ketone
group.
This aglycone ring ranges in size from 12, 14 or 16
membered rings.
O
OH
12
13
10
9
11
OH
7
OH
14
4
1
3
O
O
8
2
6
5
desosamine
cladinose
Erythromycin (1952)
To overcome the problems of bitterness
and irregular oral absorption, some modifications were
applied (Prodrugs):
1. Formation of acid salt of the basic dimethyl amino
group of the aminosugar, desosamine such as the
glucoheptonate and lactobionate (injection) the
stearate and N-lauryl sulfate salt (oral) .
2. Formation of esters of 2’ OH gp of the
desosamine sugar as ethyl succinate which is
hydrolysed in the intestine, propionate which are
hydrolysed by plasma and tissue esterase.
Erythromycin estolate (oral)
is C2`propionyl ester, N-Lauryl sulphate salt.
 Instability
of erythromycin
In acidic media a facile intra-molecular cyclization
in which the hydroxyl group at C6 adds to the
carbonyl gp at C9, forming a 6,9-hemiketal
that undergoes irreversible dehydration
(between 8&9)
Participation of the hydroxyl group at C12 in a
second intramolecular cyclization yields the
6,9, 9, 12 spiroketal, either through the
intermediate anhydrohemiketal or directly
from erythromycin.
Irreversible
Irreversible
Semisynthetic derivatives to prevent the
intramolecular reactions.
1. Roxithromycin is an example for the
conversion of the ketonic group into oxime.
(Methoxyethoxymethoxyimino)
2. Azithromycin is a modification,
9oxime gave ring expansion to a 15membered intermediate, in which a
basic nitrogen atom was embedded into
the aglycone
3. Clarithromycin
6-methyl ether of Erythromycin with marked
reduced GI side effects with markedly increased
acid stability

Mode of action (bacteriostatic):
They selectively bind to a specific site on the 50S
ribosomal subunit to prevent the translocation
step of bacterial protein synthesis. Macrolides
tend to accumulate within leukocytes, and are
therefore actually transported into the site of
infection.
Bacterial Spectrum (resembles that of
penicillins)
They are effective against most gram +ve
bacteria and some gram –ve bacteria.
Also effective against Mycoplasma, Chlamydia
and Legionella.
Often used to treat upper and lower respiratory
tract infections, and some sexually
transmitted diseases caused by mixed
infections.
Wilson and Gisvold’ s Textbook of Organic Medicinal and Pharmaceutical Chemistry
Chapter 8 Page 294
Aminoglycosides
They are produced by fermentation of actinomyces
Chemistry:
They are named amino cyclitol/aminoglycosides,
the pharmacophoric group is 1,3 diaminoinositol
1
3
Some of the alcoholic functions of these are
substituted through glycosidic bonds with
characteristic aminosugars

Streptomycin contains the aminocyclitol
Streptamine (streptidine), which is substituted
on its C-4 hydroxyl group by the branched sugar
α-L-streptose, which itself is substituted by αL-methylglucosamine.
Streptamine
α-L-streptose
Discovered in
(1952), treated TB

α-L-methylglucosamine


2-Deoxystrepamine containing
aminoglycosides includes; kanamycin,
neomycin, gentamycin, paromomycin and
tobramycin
Spectinamine containing like: Spectinomycin

Characters;
1) Potent broad spectrum bactericidal. However,
their oto and nephrotoxicity restricted their
systemic use in serious infections.
2) Freely water soluble at all pHs, basic, poorly
absorbed from GIT (less than 1%). Thus, some
of them like; kanamycin, neomycin and
paromomycin are used for GI infections. Also,
used parentrally as IM injection.
 Recently, tobramycin has been spread
successfully into the lung to treat Pseudomonas
aeruginosa in cystic fibrosis (reduced toxicity).
3) Highly excreted in the active form in urine.

Mode of action
They act directly on the bacterial ribosome to
inhibit the initiation of protein synthesis.
Bind to the 30S ribosomal subunit to form a
complex that is unable to initiate proper
amino acid polymerization. The formation
of this non sense protein destroys the
semipermeability of the bacterial cell
membrane.
Depending on their concentration they act as
bacteriostatic or bactericidal agents.

1.
2.
3.
Unclassified antibiotics
Chloramphenicol
Novobiocin
Linezolid
Wilson and Gisvold’ s Textbook of Organic Medicinal and Pharmaceutical Chemistry
Chapter 8 Page 320
Chloramphenicol
It is the first broad spectrum antibiotic, isolated
from Streptomyces venezuelae (soil) (1949).
OH
Cl
H
N
(R)
Cl
(R)
O
+
N
O
OH
O-
D-(-)-Threo-2,2-dichloro-N-[2-hydroxy-1-hydroxy
methyl)-2-(4-nitrophenyl) ethyl]-acetamide
Can you predict the light induced hydrolytic reaction in
solutions?
Products of chloramphenicol
Mechanism of action of chloramphenicol:
(BACTERIOSTATIC)

At realistic concentration each bacterial
ribosome bind 1 mol of chloramphenicol at
both 50S and 30S subunits resulting in
inhibition of the protein biosynthesis.
Ester of Chloramphenicol as prodrugs
1. Palmitate ester, (water insoluble) used in
pediatric oral suspension to mask the bitter
taste.
Ester of Chloramphenicol as prodrugs
2. Hemisuccinate ester, (very water soluble
sodium salt) used for IM or IV or
subcutaneous preparations.

Thiamphenicol (4-methyl sulphonyl)
It is quite potent, has not been associated with
aplastic anemia which is the great drawback
of using chloramphenicol due to the
formation of p-nitroso analogue.
OH
(R)
Cl
H
N
Cl
(R)
O
O
S
H3C
O
OH
Metabolism
90% is metabolized as chloramphenicol
glucoronide
2% deacetylated or dehalogenated
8% excreted unchanged
Adverse reactions
Aplastic anemia
Toxic bone marrow depression
Grey baby Syndrome
Hypersensitivity reactions

Chloramphenicol is the drug of choice in:
(1) Typhoid fever and other serious Salmonella
infections;
(2) Meningitis
(3) Serious infection caused by B. fragilis;
(4) Rickettsial infection.
 Chloramphenicol should only be used for
serious infections in which other medicines
do not work.