Tetracyclines- Medicinal chemistry, Definition,classification,SAR,Mechanism of action, Side effects, uses. By-Ravisankar.P,Vignan Pharmacy College, Vadlamudi

1. .Prof. P.Ravisankar
Vignan Pharmacy college
Valdlamudi
Guntur Dist.
Andhra Pradesh
India.
banuman35@gmail.com
00919059994000

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.Spectrum activity
10.Uses of tetracyclines
11.Side effects of tetracyclines

3. ANTIBIOTICS
DEFINITION : These are chemical
compounds or substances obtained
from various kinds of microorganisms
which destroy/inhibits the
growth of other kinds of
microorganisms at low concentration.

4. Antibiotics as disturber with the bio synthesis of
protein
● These antibiotics all target the bacterial ribosome and
interfere in the process of translation of the messenger
RNA into protein and thus block a fundamental process
in bacterial metabolism.
–Inhibitors of 30s Ribosomal subunit:
Aminoglycosides and Tetracycline’s
–Inhibitors of the 50s Ribosomal subunit:
Macrolides and Chloramphenicol

5. BACTERIAL PROTEIN SYNTHESIS INHIBITORS
BROAD SPECTRUM MODERATE SPECTRUM NARROW SPECTRUM
CHLORAMPHENICOL MACROLIDES KETOLIDES LINCOSAMIDES
TETRACYCLINES STREPTOGRAMINS
LINEZOLID

6. Tetracyclines

7. Introduction:
● Tetracyclins isolated fromStreptomyces
➢ Tetracyclines are introduced 50 years
ago as potent broad spectrum
antibiotics.
➢They are bio synthesized from acetic
acidand propionic acid units
in microorganisms.

8. At present, for many reasons such as
toxicity,drug resistance, the development
of more effectives, the uses of tetracyclines
have been largely declined.
* Tetracyclines possess a wide spectrum of
activity i.e. gram+ve and gram-ve bacteria.
* They are mainly designed for oral route
but parenteral and topical forms are available.

9. Classification :
Based on
Duration of action :
Short acting(half-life 6-8hrs)
Tetracycline
Chlortetracycline
Oxytetracycline
Intermediate acting(half-life12hrs)
Demeclocycline
Methacycline
Long acting(half-life is 16hrs)
Doxycycline
Minocycline
Tigecycline

10. According to source :
Naturally occurring
Tetracycline
Chlorotetracycline
Demeclocycline
Semi-synthetic
Doxycycline
Lymecycline
Meclocycline
Prodrugs:
Rolitetracycline
Lymelicycline
Pipacycline
Guamecycline

12. Historical background
● In 1945 Chlortetracycline(prototype)
of tetracyclines was discovered by
Dr.Benjamin,M.Duggar,under the
guidance of yellapragada subba Rao.
● 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.

13. He discovered many life saving drugs.
Deficiency of Vitamin B-12 (folic Acid) causes several
diseases.
 He succeeded in making folic acid in the laboratory.
He discovered Aureomycine.
 He was the first to discover Gramicidine.
 Subbarao discovered Methotrexate a medicine against
cancer.
Hetrazan(Diethyl carbamazine)the cure for elephantiasis.
All students of biochemistry know for his pioneering work
on protiens. This is now test book material.
 This Fisco Subbarao method got recognition amongst the
world famous scientists.
 He would have discovered many more medicines.
But one wonders why he wasn’t awarded the Nobel Prize!

15. Chemistry
The basic tetracycline structure consists
of four benzene rings with various
constituents on each ring.
The crystalline bases are faintly yellow,
odorless, slightly bitter compounds.
They are only slightly soluble in water at
pH 7 but they can form soluble sodium
salts and hydrochloride.

16. STRUCTURE
Steriochemistry of tetracycline s is very complex.

18. Tetracycline pharmacophore and
numbering
● Positions at the “bottom” of
the molecule (10, 11, 1) and
most of ring A (positions 2, 3,
and 4) represent the invariant
pharmacophore region of the
molecule, where modifications
are not tolerated without loss
of antibiotic activity.

20. 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
O O
OH
NH2
C
H3C OHH
OOH OH
OH
CH3H3C
N
121110
9
8
7
6
5
4
3
2
1
MECLOCYCLINE
Meclan
MINOCYCLINE
Arestin, Dynacin,
Vectrin, Minocin
METHACYCLINE
[Rondomycin]
DOXYCYCLINE
Vibramycin, Vibra–Tabs
Doryx, Doxy,
DEMECLOTETRACYCLINE
Declomycin
OXYTETRACYCLINE
Terramycin, (Urobiotic)
CHLORTETRACYCLINE
Aureomycin
TETRACYCLINE
Achrommycin, Sumycin,
Panmycin, Teracap, Tetracyn, Tetralan
TIGECYCLINE
Tygacil™

21. The keto-enol tatomerism
Between c2 and c3 are very
important for biological
activity.
‘D’ ring should be
always aromatic
Changes in this ring
Leads to biological
inactivation of the molecule. Conversion of
corboxamide group to
nitriles cause a 20 fold
loss of activity.
Epimerization at c4
and dehydration at 5a
results loss of activity.
Elimination of 6-OH group
Causes increase lipophilicity
And more stable to acids.
Ex: Doxycycline.
The linearly fused tetracyclic
nucleus is most important
for the antibiotic activity.
Inviolate zone is essential
Little information
available.
Substitution of
-N(CH3)2 at 7
increase the activity.
Ex: Minocycline.
(=CH2 at c6 increases the
Antibacterial activity Ex: Methacycline).
(any modification at
C3 loss of activity.)
Electron donating (or)
electron withdrawing
groups at c7 increased
Antibacterial activity Substitution with –OH Produce water soluble
derivatives which can
be administered orally.
Additional glycyl amino
substitution at the 9th
Position leads to the new
Class of antibiotics
the glycylcyclines.
EX: Tigecycline.(Tygacil)
Presence 0f-N(CH3)2 group at
C4 Tetracyclines exists Ziwitter ion
Which can be posible to distribute in
The body.Removal of this group loss
of activity.
Replacement of –No2 group Gives
more potent but carcinogenic compounds.
ABCD

22. SAR summarization

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

24. AMPHOTERIC NATURE
3 structural units (3 groups are responsible for the
amphoteric nature of tetracyclines.
Amphoteric nature of tetracycline’s:
The tetracyclines are amphoteric compounds.
Amphoteric, meaning they will form salts with both
strong acids and bases.
Thus, they may exist as salts of sodium or chloride.
Three structrual units of tetracyclines reprasenting
3pka values.
Pka1--- Conjugated trione system extending from C1 to C3
of ring A is acidic nature of Pka 2.8-3.4.

25. 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 substituent's 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.

26. ●One of the important property of tetracyclines is their ability to undergo
epimerisation at C4 position.
●Under acidic condition, tetracycline decline to the elimination reaction of giving off
H2O from the C-6 hydroxyl and C-5a hydrogen to generate the inactive 4-
epitetracyclines.

27. Most of the natural tetracyclines have tertiary benzylic hydroxyl group at c-6.
Aromatization of ring C under acidic condition occurring as a result of
dehydration reaction, which is accelerated by elevated temperatures. The
elements of H2O derive from the 6-OH and 5a-H atom.
6
5a
-H2o
-H2o
(acid)
ABCD
(Napthalene derivative)

28. ●Putting the tetracyclines in a basic solution leads to
cleavage of ring C from ring B, which leads to the
formation of inactive isotetracycline.
Isotetracycline
OH-
-H20

30. ●Chelation is an important feature of the chemical and clinical properties of the
tetracyclines.
●Tetracyclines are able to form complexes with divalent and trivalent metal ions
such as Ca2+,Fe2+,Mg2+,Al3+,Fe3+

31. 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.
. .

33. Freeze initiation
Block
peptide
bond
formatio
n
Misreading of mRNA
p-Site
(Peptidyl site)
on which the
t-RNA holds the
Elongated peptide chain.
(A-site)
Amino acetyl
t-RNA binding
site.(attachment of
Incomming amino
Acid by t-RNA.
(Aminoglycosides
blocks translocationhere)
Chloramphenical
Blocks transpeptidation
Tetracyclines reversibly
bind to the 30S subunit
at the A-site to prevent
attachment of the
amino acyl tRNA,
terminating the
translation process.

34. What are spectrum of activity of
Tetracyclines?
Tetracyclines are effective against G+ and G
① They are weaker than penicilins and
cephalosporins against G+ organisms.
② They are weaker than aminoglycosides
and chloramphenicol against Gram(+,-)
organisms.

35. Spectrum of activity:
③ They have the favourable effects on
* Rickettsiae,
* Mycoplasma,
* Chlamydiae
* Spirochete.
④ They are effective against some
protozoa.

36. Clinical Uses
① First choice for rickettsial infections
(typhus), chlamydial infections, and
Mycoplasma pneumonia.
② They are effective for many spirochetal
infections, including relapsing fever (first
choice), leptospirosis, Lyme diseases, and
syphilis.

37. ③ They are also effective for treatment of
various G+ and G- bacterial infections.
Brucellosis, cholera, and tularemia can be
treated with tetracyclines as the first
choice.
④ Other uses: intestinal amebiasis, acne and
Actinomycosis ect...

38. Adverse Effects
Tetracyclines can produce a variety
of adverse effects ranging from
minor inconvenience to life-
threatening.

39. Gastrointestinal
• Anorexia, epigastric pain, abdominal
distention, nausea, vomiting, diarrhea,
sore mouth, perianal irritation

40. Hepatic Toxicity
Microscopic study of the liver reveals
fine vacuoles, cytoplasmic changes and
an increase in fat. Pregnant women are
particularly sensitive to Tetracyclines -
induced hepatic damage. Jaundice (
increased UREA) azotemia, acidosis,
shock. (in pregnant women experiencing
pyelonephritis can be fatal)

41. Renal Toxicity
Tetracyclines may aggregate uremia in
patients with renal disease by I protein
synthesis - increased azotemia.
Fanconi Syndrome -observed in patients after
taking outdated and degraded Tetracycline. -
clinical picture -nausea, vomiting, polyuria,
polydipsia, acidosis, proteinuria, glycosuria

42. Effects on TEETH
Children receiving long-or short
term therapy with Tetracyclines may
develop brown discoloration of the
teeth. The drug deposits in the teeth
and bones probably due to its
chelating property and the formation
of a Tetracyclines -calcium
orthophosphate complex. This
discoloration is permanent. Avoid
giving to pregnant women and
children under the age of 8.

43. Other effects
Hyersensitivity Rxn -Rash, hives with
itching, itching anaphylactic rxn ( decrease
in BP, increase in HR, release of histamine,
etc.)
Photoxicity -1 darkening of skin &
sunburn when patient exposed to sunlight

45. Effects on Microbial Agents
The Tetracyclines possess a wide range of
antimicrobial activity against gram-positive
and gram-negative bacteria. These drugs are
primarily bacteriostatic. Only multiplying
microorganisms are affected. Minocycline is
usually the most active followed by doxycycline
then Tetracyclines and oxytetracycline (least
active). Strains inhibited by 4 ug/ml or less at
tetracyclines are considered sensitive.

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

47. * 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.
* Do not use this medication if you are pregnant..

48. 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.

49. •Medicinal and Pharmaceutical chemistry by Daniel
lednicer
• Hari Kishan Singh and V.K.Kapoor
•Principles of Organic medicinal chemistry by Ramarao
Nadendla.
•Wilson and Gisvolds text book of Organic and medicinal
chemistry.

50. •Medicinal chemistry by P.Yogeswari.
•Text book of Pharmaceutical chemistry by P.Parimoo
•Remington's Pharmaceutical sciences.
•Foye's Principles of Medicinal Chemistry
•medicinal chemistry by ashutosh kar
•Graham L.Patrick An introduction to Medicinal Chemistry