Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D.

1
TETRACYCLINS
Dr. P. Ravisankar, M. Pharm., Ph.D.
By
V. Laya Sri.
Vignan Pharmacy College, Vadlamudi, Guntur, A.P, INDIA
TETRACYCLINES

Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 2
1. Definition
2. Introduction
3. Classification
4. Historical background
5. Sources
6. Chemistry
7. SAR of tetracyclines
8. Mechanism of action of tetracyclines
9. Spectram activity
10.Uses of tetracyclines
11.Side effects of tetracyclines

Definition:
Tetracyclines are octahydro napthacene derivatives
which are bacteriostatic and broad spectrum antibiotics
that kills certain infection - causing microorganisms and
are used to treat wide variety of infections.

TETRACYCLINES
 Tetra means = Four
 Cycl means = Hyrocarbon ring
 Ine means = Derivation

Tetracyclines are introduced 50 years ago as potent broad spectrum
antibiotics.
They are biosynthesized from acetic acid and propionic acid units in
microorganisms.
Tetracyclines possess a wide specturm of acitivty i.e. gram+ve and gram-ve
bacteria.
They are mainly designed for oral route but parenteral and topical forms are
available.
Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP
5

In 1945 Chlortetracycline (prototype) of tetracyclines was
discovered by Dr. Benjamin, M. Duggar under the guidance of
Yellapragada Subba Rao.
He was born in a poor Telugu Niyogi Brahmin family in
Bhimavaram in West Godavari district, Andhra Pradesh.
He was an employee of Lederle Laboratories in U.S.A.
Dr. Duggar produced Chlortetracycline (Aureomycin) form
golden – colored soil bacterium called Streptomyces
aureofaciens by fermentation technology.
6

He discovered many life saving drugs.
 Vitamin B-12 (Cyanocobalamine).
Folic acid vitamin : A remedy medicine to cure “sprue”
 Aureomycine (world’s first Tetracycline and cure cholera, typhoid, plague
& dysentry).
 He was the first to discover Gramicidine (polypeptide antibiotic).
 Methotrexate (To prevent blood cancer in children).
Hetrazin (elephantiasis & isnophelia, filariasis).
 This Fisco Subbarao method got recognition amongst the world famous
scientists.
Isonicotinic acid Hydrazide (INH) ( To cureTuberculosis).
Discovered the role of ATP which are the sources of energy in human body.
7

According to duration of action:
Short-acting (Half-life is 6-8 hrs)
• Tetracycline Chlortetracycline Oxytetracycline
Intermediate-acting (Half-life is ~12 hrs)
Long-acting (Half-life is 16 hrs or more)
• Doxycycline Minocycline Tigecycline
• Demeclocycline Methacycline

9

Tetracyclines are obtained from various species of
Streptomyces bacteria by fermentation technology
Chlortetracycline(aureomycin)
from Streptomyces aureofaciens.
Oxytetracycline (Terramycin)
from Streptomyces rimosus.

Stereochemistry of tetracyclines is very complex.
11
4,4a,5,5a,6,12a
Methacycline , Oxytetracycline, Meclocycline, Doxycycline
possess 5-hydroxy Substituent have 6 chiral carbon atoms.
Others have only 5 chiral carbon atoms.

Important structrual units and the three acidity constants in the
tetracycline molecule.
(conjugated
Trione system
Is acidic nature)
pka1 (2.8-3.4)
(Conjugated phenolic
Enone system is slightly
basic)
Strong alkaline.
Pka (7.2-7.8) Pka3 (9.1-9.7)

O O
OH
NH2
CH3HO
C
O
OH
OHOH
CH3H3C
N
H3C
CH3
H3C
H
N
O
N
H
CH3H3C
N
O O
OH
NH2
C
OH
OHOH
CH3H3C
N
O
CH3H3C
N
O O
OH
NH2
C
OH
OHOH
CH3H3C
N
O
O O
OH
NH2
C
OHCH2
O
OH
OHOH
CH3H3C
N
N
H3C CH3
OH OH
OH
O
OH
C
HO CH3
NH2
OH
OO
N
H3C CH3
Cl
OH OH
OH
O
CH2 OH
C
NH2
OH
OO
O O
OH
NH2
CH3HO
C
Cl
OOH
OH
OH
CH3H3C
N
O O
OH
NH2
H
C
Cl HO
OOH OH
OH
CH3H3C
N
121110
9
8
7
6
5
4
3
2
1
METHACYCLINE
[Rondomycin]
OXYTETRACYCLINE
Terramycin, (Urobiotic)
CHLORTETRACYCLINE
Aureomycin
TETRACYCLINE
Achrommycin, Sumycin,
Panmycin, Teracap, Tetracyn, Tetralan
TIGECYCLINE
Tygacil™
MECLOCYCLINE
Meclan
MINOCYCLINE
Arestin, Dynacin,
Vectrin, Minocin
DEMECLOTETRACYCLINE
Declomycin
O O
OH
NH2
C
H3C OHH
OOH OH
OH
CH3H3C
N
DOXYCYCLINE
Vibramycin, Vibra–Tabs
Doryx, Doxy
STRUCTURES OF IMPORTANT TETRACYCLINES

OH OH
CONH2
OH
R1
O O
R2
R3
H
R4
H
N(CH3)2
OH
ABCD
1
2
3
4
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
N(CH3)2 Increases
activity
Conversion to nitriles
causes a 20 fold increase
in activity
Modification leads
to loss of activity
=CH2 Increases the
Antibacterial activity
Elimination of 6-OH group
increase lipophilicity
& more stable to acids.
Ex: Doxycycline.
‘D’ ring should be
always aromatic
Changes in this ring
Leads to biological
inactivation of the
molecule.
Additional glycyl amino
substitution at the 9th
Position leads to the new
Class of antibiotics
the glycylcyclines.
EX: Tigecycline.(Tygacil)
The keto-enol
tatomerism
Between c2 and c3 are
very
important for
biological
activity.
Inviolate zone is essential
The linearly fused tetracyclic
nucleus is most important
for the antibiotic activity.
Electron donating (or)
electron withdrawing
groups at c7 increased
Antibacterial activity
Substitution with –OH Produce water
soluble derivatives which can
be administered orally.
Epimerization at c4
and dehydration at 5a
results loss of activity.
14
Structural Activity Relationship:

SUMMARY:
OH
CONH2
OHOH
R1
R2
O O
N(CH3)2
OH
H
R4
H
R3
1
4
2
3
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
ABCD
S.NO Structural Modifications Effects
1. Any modification No bacterial activity
2. Acetyl group only Slightly activity retained
3. Any modification No bacterial activity
4. α dimethylamino group NHCH3 retains more activity
5a. Loss of H Inactive degradation product
6. Remove OH,CH3 or both More stable compound
7. Cl,Br,NO2,(CH3)2N- Activity retained
8. Little information available _
9. Cl and CH3 Decreased activity
10,11,11a,12. “Inviolate zone” including C-1 Diminished activity

Epimerization:
OH
CONH2
OHOH
HO
O O
N(CH3)2
OH
H H
CH3
1
4
2
3
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
ABCD
H H
H
OH OH
CONH2
OH
O O
N(CH3)2CH3
H
H
H
OH
-H2O
Tetracycline
(Active)
Anhydrous Tetracycline
(Inactive)
H+
H
OH
CONH2
OH
OH O
H
H
H
OH
O
HO N(CH3)2
CH3 H
4-Epi tetracycline
(Inactive)
-H2O
H
OH OH
CONH2
OH
O O
CH3
OH
H
N(CH3)2
4-Epianhydro tetracycline
(Inactive)
H+
16
Strong acids and bases
Attack those tetracyclines
Which possess an –OH group at
C-6 and form inactive
anhydrotetracyclines

Base-catalyzed instability of tracylines:
OH
CONH2
OHOH
HO
O O
N(CH3)2
OH
H H
CH3
1
4
2
3
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
ABCD
H H
OH-
-H2O
OH
CONH
2
OH
OHO O
N(CH3)2
OH
CH3H
H
H
H
O
Isotetracycline
(Inactive)
Tetracycline
17
Under alkaline condition, OH at C6 change into oxygen anion and
then attacks the C-11 (ketone group) lead to intramolecular
nuclear reaction, by electron transfer, C ring rupture to generate
inactive isotetracycline lactone.

CHELATION:
Tetracyclines
Ca2+, Fe2+
Al3+, Fe3+
Citrates
lipoproteins
Serum albumin
globulins
Metal
complexes
(Insoluble in
water at
neutral PHs)
18
This insolubility is not only inconvenient for the preparation of
solutions but also interferes with blood levels on oral administration.
 The tetracycline's are incompatible with co-administered,
multivalent ion-rich antacids and with hematinics and concomitant
consumption of daily products rich in calcium ion also is
contraindicated.

Amphoteric nature of tetracyclines:
• Tetracyclines are amphoteric compounds.
• Amphoteric = form salts with both strong acids and bases.
Three structrual units of tetracyclines representing 3pka values.
 Pka1--- Conjugated trione system extending from C1 to C3 of
ring A is acidic nature of Pka 2.8-3.4.
 Pka2--- Conjugated phenolic enone system from C10-C12 is
associated with weak basic Pka values ranging from 7.2-7.8.
 Pka3-- C4 atom and its substituents exhibits Pka3 ranging from
9.1 to 9.7. which represents strong alkaline nature.
Because of the amphoteric nature tetracyclines forms water soluble salts
with strong acids such as HCl and strong bases such NaOH, KOH.
19

 Tetracyclines inhibit protein synthesis by binding to the bacterial ribosome involved
in the translation(protein synthesis) process and making them bacteriostatic.
 The bacterial ribosome is a 70s particle made up of 30s subunit and 50s subunit.
 The 30s subunit binds mRNA and initiates the protein synthesis.
 The 50s subunit combines with the 30s subunit-mRNA complex to form a ribisome
then binds aminoacyl tRNA and catalyses the building of the protein chain..
 There are two main binding sites for the tRNA molecule.
 The peptidyl(p-site) binds the tRNA bearing the peptide chain
 The acceptor aminoacyl site (A-site)
 Tetracyclines reversibly bind to the 30S subunit at the A-site to prevent attachment
of the amino acyl tRNA, terminating the translation process.
. .
20

21

Animation Illustrating the Role of Tetracyclines in Blocking Translation
during Bacterial Protein Synthesis

 Gram +ve & -ve bacteria
 Spirochetes
 Mycoplasms
 Rickettsiae
 Candida Albicans
 Mycoplasma Pneumoniae
 Chlamydia Trachomatis
 Borrelia Recurrentis
 Yersinia Pestis
 Vibrio Cholerae
 Campylavacter Fetus
 Brucella Specie
 Streptococcus Pneumonia
 Neisseerie Gonorrhoeae
23
• Tetracyclines are broad spectrum antibiotics.
They are active against following micro organisms:

• Tetracyclines are called "broad-spectrum" antibiotics, because they can
be used to treat a wide variety of infections.
• Physicians may prescribe these drugs to treat eye infections.
• Tetracyclines are generally a low-cost alternative among antibiotics.
• Interestingly, a form of tetracycline has recently been used in
prevention of cancer recurrence.
• Tetracyclines may be used in the treatment of infections of the
respiratory tract, sinuses, middle ear, intestines.
• Gonorrhoea
24

• Acne Rosacea
• Acne vulgaris
• Actinomyces Israelii
• Actinomycosis
• Anthrax
• Bacillus Anthracis
• Bacterial Conjunctivitis
• Balantidium coli
• Bartonella Bacilliformis
• Bartonellosis
• Bordetella Pertussis
• Borrelia Burgdorferi
• Borrelia Recurrentis
• Bronchitis- acute
• Brucella Sp.
• Brucellosis
• Burkholderia Mallei
• Burkholderia Pseudomallei
• Campylobacter Fetus
• Cervicitis
• Chancroid
• Chlamydia Psittaci
• Chlamydia Trachomatis
• Chlamydial Conjunctivitis
• Chlamydia Trachomatis
• Chlamydial Conjunctivitis
• Clostridium Tetani
• Coxiella Burnetii
25

• Duodenal Ulcer
• Entamoeba
Histolytica
• Francisella Tularensis
• Fusobacterium Fusiforme
• Gonorrhea
• Granuloma Inguinale
• Haemophilus Ducreyi
• Haemophilus Influenzae (beta-
lactamase Negative)
• Haemophilus Influenzae (beta-
lactamase Positive)
• Helicobacter Pylori
• Klebsiella Granulomatis
• Legionella Pneumophila
• Leptospira Sp.
• Leptotrichia Buccalis
• Listeria Monocytogenes
• Lower Respiratory Tract Infections
• Lymphogranuloma Venereum
• Murine Typhus
• Mycobacterium Fortuitum
• Mycoplasma Hominis
• Mycoplasma Pneumoniae
• Neisseria Gonorrhoeae
• Neisseria Meningitidis
• Nocardia Sp.
• Non-gonococcal Urethritis (NGU)
• Ophthalmia Neonatorum
Prophylaxis
• Otitis Media
• Pasteurella Multocida
• Periodontitis
• Pharyngitis

;’
• Plague
• Plague Prophylaxis
• Plasmodium Falciparum
• Pneumonia
• Proctitis
• Propionibacterium Acnes
• Propionibacterium Propionicum
• Psittacosis
• Q Fever
• Relapsing Fever
• Rickettsia Akari
• Rickettsia Prowazekii
• Rickettsia Rickettsii
• Rickettsia Tsutsugamushi
• Rickettsial Pox
• Rocky Mountain Spotted Fever
• Shigella Sp.
• Shigellosis
• Sinusitis
• Skin And Skin Structure Infections
• The tetracyclines will not work for colds, flu, and
other infections caused by viruses
• Spirillum Minus
• Streptobacillus Moniliformis
• Syphilis
• Treponema Pallidum
• Tularemia
• Upper Respiratory Tract Infection
• Ureaplasma Urealyticum
• Urinary Tract Infection
• Vibrio Parahaemolyticus
• Yaws
• Yersinia Enterocolitica
• Yersinia Pestis
• Amebiasis
• Anthrax Prophylaxis
• Bejel
• Biliary Tract Infections
• Cholera
• Dentoalveolar Infection
• Dyspepsia
• Endodontic Infection
• Enterocolitis
• Gastric Ulcer
• Legionnaire's Disease
• Lyme Disease
• Malaria
• Pinta
• Tertiary Syphilis

Contraindications of Tetracycline Antibiotics :
 Can stain developing teeth (even when taken by the mother during
pregnancy)
 Inactivated by Ca2+ ion, not to be taken with milk, yogurt, and other dairy
products.
 Skin photosensitivity; exposure to the Sun or intense light is not
recommended
 Drug-induced lupus, and hepatitis
 Can induce microvesicular fatty liver.
 May interfere with methotrexate by displacing it from the various protein
binding sites
29
:

• Tetracyclines should therefore
be avoided in pregnant or
lactating women.
• Tetracycline might cause
stains to developing adult
teeth,which cannot be easily
removed with conventional
tooth whitening.
• Tetracycline can
cause skin reaction.
30

• Mild nausea, vomiting, diarrhea.
• White patches or sores inside your
mouth or on your lips .
• Swollen tongue, trouble swallowing.
• Vaginal itching or discharge.
• Loss of appetite, jaundice (yellowing
of the skin or eyes).

• Cholesterol-lowering medications such as cholestyramine
(Prevalite, Questran) .
• Isotretinoin (Accutane).
• Tretinoin (Renova, Retin-A, Vesanoid) .
• A blood thinner such as warfarin (Coumadin).
• A penicillin antibiotic such as amoxicillin (Amoxil, Trimox,
others).
• Penicillin (BeePen-VK, Pen-Vee K, Veetids, others).
• Dicloxacillin (Dynapen)
32

33
 Finish the prescription.
 Take on empty stomach.
 Take with plenty of water.
 Shake well.
 Do not take with milk, antacids, or iron
.
 Avoid exposure to sun.

34
 Do not use this medication if you are pregnant..
 Tetracycline passes into breast milk and may affect bone and tooth
development in a nursing baby.
 Do not give tetracycline to a child younger than 8 years old.
 Avoid exposure to sunlight or artificial UV rays.
 Do not take iron supplements, multivitamins, calcium supplements,
antacids.
 Throw away any unused tetracycline when it expires or when it is
no longer needed.

• KEY POINTS
• The tetracyclines are bacteriostatic antibiotics that have a broad spectrum of activity and are the most widely
prescribed form of antibiotic after penicillins.
• The tetracyclines are broad-spectrum antibiotics that are active against both Gram-positive and Gram-negative
bacteria.
• The tetracyclines inhibit protein synthesis by binding to the 30S subunit of ribosomes and preventing aminoacyl-
tRNA from binding. This stops the further addition of amino acids to the growing protein chain. Protein release is
also inhibited.
• The tetracyclines were originally used for many types of respiratory infections, but have been largely replaced by
beta-lactams because of the problems of resistance. However, they are still the agents of choice for the treatment of
Lyme disease, rickettsia, and infections caused by chlamydia.
• They are also used to treat acne and a variety of different infections including respiratory and genital infections.
Doxycycline has been found to be useful for the treatment and prophylaxis of malaria, and is cheaper than other
antimalarial agents.
• The drug can also be used for the treatment of a variety of diseases including syphilis, sinusitis, oral herpes simplex,
and acne. It is a possible agent for the treatment or prophylaxis of anthrax.
• Tetracyclines should be avoided for young children and pregnant mothers since they can bind to developing teeth
and bone, leading to tooth discolouration.
• Resistance to tetracyclines can arise through several mechanisms. Some organisms have effective efflux
mechanisms that pump the drug back out of the cell. Resistance can also arise from alterations in the bacterial
ribosomes, such that they have lower affinity for the agents.
•
Vignan Pharmacy
College,Vadlamudi,Guntur.dst,AP
35

36

37
• D. Sri Ram, P. Yogeswari., Medicinal Chemistry;
2nd Edition;316-321.
• K.Illango , P. Valentina., Text book of Medicinal Chemistry;
vol-II;150-158.
• Dr. S. S. Kadam., Principles of Medicinal Chemistry;
Vol-I;5.26.
• Wilson and Gisvold’s., Text book of Organic Medical and
Pharmaceutical Chemistry;12th Edition;341-348.

38
• G. L. Patrick., Introduction to Medicinal Chemistry
• William O. Foye., Textbook of Medicinal Chemistry,
Lea & Febiger , Philadelphia.
• S. N. Pandeya., Medicinal Chemistry; Vol-II; 837-850.
• Rama Rao., Medicinal Chemistry ; 120 – 124.

39

Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D.

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D.

Similar to Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D. (20)

More from Dr. Ravi Sankar

More from Dr. Ravi Sankar (20)

Recently uploaded

Recently uploaded (20)

Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D.