Tetracyclines are potent, broad-spectrum
antibacterial agents effective against gram-positive and
gram-negative,aerobic and anaerobic bacteria. As a
result, the tetracyclines are drugs of choice or well-
accepted alternatives for a variety of infectious
Tetracyclines have a ring system of four linear
annelated six-membered rings and are characterized by
a common octahydronaphthacenes skeleton.
I. Natrual tetracyclines (biosynthetic)
II. Semisynthetic tetracyclines
6. MECHANISM OF ACTION
Inhibition of protein synthesis. Once tetracyclines have
been transported into the cell, this class of antibiotic
reversibly binds to receptors on the 30S ribosomal
subunit of the bacteria, preventing attachment of
aminoacyl-tRNA to the RNA-ribosome complex.
9. Modification of C-1 and C-3 position:
The keto-enol tautomerism of ring A in carbon atom 1 and 3 is a common
feature to all biologically active tetracyclines, blocking this system by forming
derivatives at C-1and C-3 results in loss of antibacterial activity.
Modification of C-2 position:
The antibacterial activity resides on the carboxamide moiety. The amide is
best left unsubstituted or monosubstitution is acceptable in the form of activated
alkylaminomethyl amide. The replacement of carboxamide group or dehydration
of carboxamide to the corresponding nitrile results in a loss of activity.
10. Modification of C-4 position:
The keto-enolic character of the A-ring is due to the α-C-4 dimethyl amino
substituent. Loss of activity is exerted when dimethyl amino group is replaced with
hydrazone oxime or hydroxyl group.
Modification of C-4a position:
The α-hydrogen at C-4a position of tetracyclines is necessary for useful
Modification of the C-5 and C-5a positions:
Alkylation of the C-5 hydroxyl group results in loss of activity.Naturally occurring
antibacterial tetracyclines have an unsubstituted methylene moiety at the C-5
position.However, oxytetracycline contains C-5 α-hydroxyl group, was found to be a
potent compound.Esterification is only acceptable if the free oxytetracycline can be
liberated in vivo. Epimerization is detrimental to antibacterial activity.
11. Modification at the C-6 position:
The C-6 methyl group contributes little to the activity of tetracycline.The
majority of tetracyclines have α-methyl group and α β-hydroxyl group at this
position. Demeclocyclin is a naturally occurring C-6 demethylated chlortetracycline
with an excellent activity. Removal of C-6 hydroxyl group affords doxycycline,
which exerts good antibacterial activity.
C-7 and C-9 substituents:
Substitution with electron withdrawing group such as nitro and halogen groups
are introduced which produces the most potent of all the tetracyclines in vitro, but
there are compounds are potentially toxic and carcinogenic. The C-7 acetoxy,
azido, and hydroxyl tetracyclines are inferior in terms of antibacterial activity.
The C-10 phenolic moiety is necessary for antibacterial activity. C-10 substitution
with para or ortho hydrogen group activates the C-9 and C-7.
12. C-11 substituents:
The C-11 carbonyl moiety is a part of one of the conjugated keto-enol system
required for antibacterial activity.
No stable tetracyclines are formed by modifications at the C-11a position.
Esterification of the hydroxyl group leads to the incorporation of drug with
the tissues due to the enhanced lipophilicity and it should undergo hydrolysis to
leave the active tetracycline with hydroxyl group at 12a position, which is
necessary to produce good antibacterial action. The transport and binding of
these drugs depends on keto-enol system.
Tetracycline is used to treat infections caused by bacteria including pneumonia and other
respiratory tract infections; certain infections of skin, eye, lymphatic, intestinal, genital
and urinary systems.
Nausea, vomiting, diarrhea, loss of appetite, mouth sores, sore throat, dizziness,
headache, or rectal discomfort may occur.
The aminoglycoside antibiotics contain one or more
amino sugars linked to an aminocytitol ring by glycosidic
bonds. These are broad-spectrum antibiotics; in general,
they have greater activity against gram-negative than
16. MECHANISM OF ACTION
The aminoglycosides exhibit bactericidal effects as a
result of several phenomena.
Ribosomal binding on 30s and 50s subunits as well as
the interface produces misreading; this disturbs the
normal protein synthesis.
Cell membrane damage also plays an integral part in
ensuring bacterial celldeath.
Aminoglycosides are used in the treatment of severe infections of the abdomen and
urinary tract, as well as bacteremia and endocarditis. They are also used for prophylaxis,
especially against endocarditis.
The aminoglycoside can produces severe adverse effects, which include nephrotoxity,
ototoxicity, and neuro effects.
The macrolide antibacterial agents are extremely useful
chemotherapeutic agents for the treatment of a variety of
infectious disorders and diseases caused by a host of gram-
positive bacteria, both cocci and bacilli; they also exhibit useful
effectiveness against gram-negative cocci, specially, neisseria
21. MECHANISM OF ACTION
Macrolide antibiotics are bacteriostatic agents that inhibit
protein synthesis by binding irreversibly to a site on the 50S
subunits of the bacterial ribosome. Thus, inhibiting the
translocation steps of protein synthesis at varying stages of
peptide chain elongation. The macrolides inhibit ribosomal
peptidyl transferase activity.Some macrolides also inhibit the
translocation of the ribosome along with the mRNA template.
24. SAR OF MACROLIDE
As macrolides are unstable in acidic pH, a no.of strategies
have been utilized to improve the acidic stability of erythromycin.
The addition of hydroxylamine to the ketone to form
oxime,which improves the acid stability.Eg:Roxithromycin
Alteration of c-6 hydroxyl group which is the nucleophilic
functionality which initiates erythromycin degradation.
Addition of nitrogen atom to expand a 14-membered
precursor– leads to an extended spectrum of action
Macrolide antibiotics can be used to treat respiratory
infections, which include pneumonia, pharyngitis, sinusitis, and
bronchitis. This class of antibiotics can also be used to treat
gastrointestinal tract, ear, and skin infections, as well as sexually
Minor side effects of macrolides include nausea, vomiting,
diarrhea, and ringing or buzzing in the ears (tinnitus). Serious side
effects, including allergic reaction and cholestatic hepatitis.
Chloramphenicol (chloromycetin) is a levorotatory
broadspectrum antibiotic originally produced from several
streptomycetes, namely : S. venezualae, S. phacochromogenes . It
has been reported to be the drug of choice for the treatment of
typhus and typhoid fever.
29. MECHANISM OF ACTION
Chloramphenicol is a bacteriostatic by inhibiting
protein synthesis. It prevents protein chain elongation
by inhibiting the peptidyl transferase activity of the
bacterial ribosome. It specifically binds to A2451 and
A2452 residues in the 23S rRNA of the 50S ribosomal
subunit, preventing peptide bond formation.
32. SAR OF CHLORAMPHENICOL
a. Modification of p-nitrophenyl group.
b. Modification of dichloroacetamide side chain.
c. Modification of 1, 3-prepanediol.
33. Modification of p-nitrophenyl group:
The p-nitrophenyl group may be modifi ed through the following ways:
a. Replacement of the nitro group by other substituents leads to a reduction in
b. Shifting of the nitro group from the para position also reduces the antibacterial
c. Replacement of phenyl group by the alicyclic moieties results in less potent
Modification of dichloroacetamido side chain:
Other dihalo derivatives of the side chain are less potent although major activities
Modification of 1,3-propanediol:
If the primary alcoholic group on C-1 atom is modified, it results in a decrease in
activity; hence, the alcoholic group seems to be essential for activity
Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial
infections. This includes use as an eye ointment to treat conjunctivitis.It is also used to
treat meningitis, plague, cholera, and typhoid fever.
Aplastic anemia,bone marrow suppression,diarrhea,inflammation of the small intestine
and the colon (enterocolitis),gray syndrome,headache,nausea
Dose: Usual adult dose is 500 mg every 6 h.
Dosage forms: Chloramphenicol capsules I.P., B.P., Chloramphenicol ear drops I.P., B.P.,
Chloramphenicoleye ointment I.P., B.P., Chloramphenicol eye drops B.P.
Text book of medicinal chemistry-V.Alagarsamy