Tetracyclines, aminoglycosides, and macrolides are classes of antibiotics that affect bacterial protein synthesis. Tetracyclines comprise a linear tetracyclic nucleus with various functional groups and differ from each other by chloride, methyl, and hydroxyl groups. Aminoglycosides contain glycosidically-linked aminosugars and demonstrate bactericidal activity against Gram-negative bacteria. Macrolides consist of a macrocyclic lactone ring with attached deoxy sugars and have antibiotic activity; their structures allow for various modifications that can enhance acid stability and spectrum of action.
1. Glimpses of
Antibiotics affecting protein synthesis
Medicinal Chemistry III
Ms. Mandakini S.Holkar
(M. Pharm.)
For Third Year B. Pharm. Program as per
PCI syllabus, New Delhi
2. Antibiotics affecting protein synthesis:
“These are the antibiotics affects protein
synthesis process of bacteria and inhibits
bacterial growth.”
Ex-
•Tetracycline and
•Aminoglycosides.
•Macrolides,
3. Tetracyclines are a group of broad-spectrum antibiotic compounds
that have a common basic structure and are either isolated directly
from several species of Streptomyces bacteria or produced semi-
synthetically from those isolated compounds
Tetracycline molecules comprise a linear fused tetracyclic nucleus
(rings designated A, B, C and D) to which a variety of functional
groups are attached Tetracyclines are named for their four ("tetra-")
hydrocarbon rings ("-cycl-") derivation ("-ine").
A. Tetracycline
4. While all tetracyclines have a common structure, they differ from
each other by the presence of chloride, methyl, and hydroxyl groups.
These modifications do not change their broad antibacterial activity,
but affect pharmacological properties such as half-life and binding to
proteins in serum.
Tetracyclines were discovered in the 1940s and exhibited activity
against a wide range of microorganisms including gram-positive and
gram-negative bacteria, mycoplasmas, rickettsiae, and protozoan
parasites.Tetracycline itself was discovered later than
chlortetracycline and oxytetracycline but is still considered as the
parent compound for nomenclature purposes.
6. Structure Activity Relationship As the name indicates, tetracycline is an
inflexible skeleton of four rings, contains many groups such as alkyl, hydroxyl
and amine on the upper and lower sides of the molecule.
Tetracycline and its analogues have basic chemical structure consisting
tetracyclic naphthacene carboxamide ring system.
Tetracyclines which illustrate antibiotic activity have a dimethylamine group
at C4 in the ring A, whose existence is necessary to show antibiotic properties.
Addition or removal of the dimethylamino group from C4 gives several
chemically modified tetracyclines .
SAR of Tetracyclines
7. Antibiotic and non-antibiotic characteristics of tetracyclines may be
reduced by modifying the lower peripheral zone; on the other hand,
modification in the upper peripheral zone enhanced the attack on biological
targets, particularly at positions C7 through C9 of the D ring.
This has been lead toward the formation of semi-synthetic compounds such
as minocycline and doxycycline .
Bioactivity, strength, selectivity to biological target and antibacterial
action, specifically against Gram- positive/negative bacteria, highly depend
upon modifications in the groups of lower and upper pheripheral zones of the
tetracycline skeleton.
8. The presence of an amino group in position C4 and ketoenolic tautomers in
position C1 and C3 of the A ring is necessary for tetracycline to take action as
inhibitor of protein synthesis.
The presence of the amino group in the C4 position is vital for antibiotic
activities
Antibacterial activity against Gram-negative bacteria may be decreased by
epimerization of natural 4S isomer of C4-dimethlyamino group to its 4R isomer.
It also requires a C10-phenol and C11-C12 keto-enol substructure in conjunction
with a 12a-OH group in the lower peripheral region.
An active tetracycline which demonstrates
antibacterial activity must have linearly arranged
DCBA naphthacene ring system with an A-ring
C1-C3 diketo substructure and an exocyclic C2
carbonyl and amide group.
9. Some modifications cause loss of potency like modification of amide in C2.
Chemical modification of the positions C5 to C9 gives various derivatives of
tetracyclines with varying antibacterial activities.
Modification of R1, R2, R3 groups gives better selectivity to the biological
target in antifungal but not for antibacterial activity.
The D-ring is most flexible to change by showing antibacterial activity.
10.
11. B. Aminoglycosides
Streptomycin, gentamicin, and neomycin are examples of
aminoglycoside antibacterials. These broad-spectrum antibiotics
are able to interfere with bacterial protein synthesis.
Aminoglycosides antibacterials contain glycosidically-linked
aminosugars.
Streptomycin, the first antibiotic of this group.
Aminoglycoside antibiotics display bactericidal activity against
Gram-negative aerobes and some anaerobic bacilli
Ototoxic and nephrotoxic effects associated with aminoglycoside
use restricted systemic use for serious infections.
13. The aminoglycosides consist of two or more amino sugars joined in
glycoside linkage to a highly substituted 1,3- diaminocyclo hexane
which is a centrally placed ring. The ring is a 2-deoxy streptamine in
all aminoglycosides except streptomycin and dihydrostreptomycin,
where it is streptidine. Thus,
In kanamycin and gentamycin families, two amino sugars are
attached to 2-deoxy streptamine.
In streptomycin, two amino sugars are attached to strepidine.
In neomycin family, there are three amino sugars attached to 2-
deoxy streptamine.
The aminoglycoside antibiotics contain two important structural
features.
They are amino sugar portion and
centrally placed hexose ring, which is either 2-deoxystreptamine
or streptidine.
14. Amino sugar portion
•The bacterial inactivating enzymes targets C-6 and C-2 position and
the substitution with methyl group at C-6
increases the enzyme resistance.
•Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not
affect the activity.
15. Centrally placed hexose ring
Various modifi cations at C-1 amino group have been tested.
The acylation (e.g. amikacyn) and ethylation (e.g. 1-N-
ethylsisomycin) though does not increase the activity helps to
retain the antibacterial potency.
In sisomicin series, 2-hydroxylation and 5-deoxygenation
result in the increased inhibition of bacterial inactivating
enzyme systems. Thus, very few modifications of the central
ring are possible, which do not violate the activity spectrum of
aminoglycosides.
16. •Streptomycin:
•It is used in the treatment of infections caused by gram-negative bacteria of
particular interest and has a high degree of activity against P. aeruginosa, where
the important causative factor is burned skin. It is used topically in the treatment
of infected bed-sores, pyodermata, burns, and in the eye infection.
17. The macrolides are a class of natural products that consist of a large
macrocyclic lactone ring to which one or more deoxy sugars, usually
cladinose and desosamine, may be attached. The lactone rings are usually
14-, 15-, or 16-membered.
Some macrolides have antibiotic or antifungal activity and are used as
pharmaceutical drugs.
Introduction
C. Macrolides
20. SAR
The two sugars attached to the ring were important too, because
removing either or both of them resulted in an inactive compound
Modifications of the dimethylamino group of the desosamine sugar
affect the potency
while the orientation of the cladinose moiety seems to be important
too.
21. Cladinose at C3 gives good activity removal of C3 –reduces the activity
C2 Fluoro group enhance the activity.
Position no-9 oxime essential for activity.
C-13 modification with selected group provides comparable spectrum
activity.
Activity strongly depends up an substitution at C-6
Addition of nitogen atom to expand a 14-membred precursor leads to an
extended spectrum of action eg. Azithromycin
22. Erythromycin is the first macrolide antibiotic.
Erythromycin is a metabolite of a strain of Streptomyces erythreus
Erythromycin contains a 14-membered lactone ring and two sugars,
desosamine (attached at C5) and cladinose (attached at C3).
Erythromycin remains one of the most widely used macrolide antibiotics
in clinical settings.
Desosamine
Cladinose
23. Structural modifications have been made to erythromycin to
augment acid-stability, as is the case with clarithromycin. The
key difference between erythromycin and clarithromycin is
that the C6 hydroxyl in erythromycin has been converted to
an ether in clarithromycin. Due to this modification,
clarithromycin has greater acid stability than erythromycin.
The other semi-synthetic derivatives, roxithromycin and
azithromycin, also have enhanced acid-stability
25. Reference:
Willams and Thomas L.Lemke Foye’s Principles of
Medicinal Chemistry Fifth edition
Rang H.P. and Dale M.M.: Pharmacology, Churchill
Livingstone, Edinbergh.
Dr.S.S.Kadam and K.R.Mahadik Principles of Medicinal
Chemistry Volume -I