2. Definition: An antibiotic is a type of antimicrobial substance used to treat bacterial
infections by inhibiting the growth or killing bacteria.
Discovery: Antibiotics were first discovered in the early 20th century, with the
pioneering work of scientists like Alexander Fleming, who discovered penicillin.
Mechanism of Action: Antibiotics target specific bacterial structures or metabolic
pathways, disrupting bacterial growth and replication without harming human cells.
Importance: Antibiotics have revolutionized medicine by significantly reducing the
morbidity and mortality associated with bacterial infections, making many previously
fatal diseases treatable.
What is an Antibiotic?
3. Introduction to Tetracyclines
Tetracyclines are a group of broad-spectrum
antibiotics that were first discovered in 1945. They
are known for their effectiveness against many
types of bacteria, making them a valuable tool in
fighting bacterial infections. The versatility and
wide-ranging effects of tetracyclines have led to
their widespread use in both human and veterinary
medicine.
4. Historical Background
1 Discovery by Benjamin Minge Duggar
Tetracyclines were first discovered in 1945 by the American botanist and bacteriologist Benjamin
Minge Duggar. His pioneering work led to the identification of these powerful antibiotics and laid the
foundation for further research and development in the field of antibacterial therapy.
2 Isolation from Streptomyces aureofaciens
The breakthrough came when tetracyclines were isolated from the bacterium Streptomyces
aureofaciens by Duggar. This discovery provided the foundation for the mass production of these
antibiotics and their subsequent use in medical applications.
3 Revolutionizing Antibiotic Therapy
The identification and isolation of tetracyclines marked a turning point in antibiotic therapy, as they
offered a broad-spectrum solution for treating a wide range of bacterial infections. This development
significantly improved the management and control of infectious diseases.
5. Nomenclature of Tetracyclines
• The nomenclature of tetracyclines is based on their distinctive four-ring structure.
The parent molecule, comprising four fused rings, serves as the core scaffold for
various derivatives and analogs. This structural feature is central to their antibiotic
activity and pharmacological properties.
Tetracycline structure
6. Nomenclature Rules
• Chemical Structure: Tetracyclines are polycyclic compounds characterized by a four-ring system consist
of Octahydronaphacene nucleus in structure.
• Prefix: Tetracycline compounds are often prefixed with the word "tetracycline" followed by specific
modifiers to differentiate between different derivatives.
• Numbering System: The tetracycline ring system is numbered conventionally from C1 to C12, with
specific substituents attached to different positions on the rings.
• Examples: Common tetracycline derivatives include tetracycline, oxytetracycline, chlortetracycline,
minocycline, and doxycycline, each with distinct structural modifications and functional groups.
• Chemical Substituents: The names of tetracycline derivatives often reflect the nature and position of
chemical substituents on the tetracycline ring system, providing information about their pharmacological
properties and spectrum of activity.
7. Examples of Tetracycline Nomenclature
•Tetracycline: The parent compound with no additional modifications to the basic tetracycline
structure.
•Oxytetracycline: Contains an oxygen atom (oxy) at position C5 of the tetracycline ring system.
•Chlortetracycline: Contains a chlorine atom (chlor) at position C7 of the tetracycline ring
system.
•Minocycline: Contains a dimethylamino group (mino) at position C7 of the tetracycline ring
system.
•Doxycycline: Contains a dimethylamino group (doxy) at position C7 and a keto group (cycline)
at position C6 of the tetracycline ring system.
8.
9. This family of antibiotics is characterized by a highly functionalized, partially reduced
octahydronaphthacene (four linearly fused, 6-membered rings) ring system, from which both
the family name and the numbering system are derived.
The tetracyclines are amphoteric compounds, i.e., forming salts with either acids or bases. In
neutral solutions these substances exist mainly as Zwitter ions. The hydrochloride salts are
used most commonly for oral administration and usually are encapsulated owing to their bitter
taste.
Octahydronaphthacene ring system
10. Stereochemistry :
The stereochemistry of the tetracyclines is very complex. Carbon atoms 4, 4a, 5, 5a, 6, and 12a are
potentially chiral, depending on substitution. Oxytetracycline and doxycycline, each with a 5α-hydroxyl
substituent, have six asymmetric centers; the others, lacking chirality at C-5, have only five.
An interesting property of the tetracyclines is their ability to undergo epimerizaton at C-4 in solutions
having intermediate pH range. These isomers are called epitetracyclines.
11. It has been observed that the strong acids and bases attack the tetracyclines having a hydroxy
moiety at C-6, thereby causing a considerable loss in activity through modification.
Strong acids produce dehydration
through a reduction involving the
OH group at C-6 and the H atom at
C-5a. The double bond thus
generated between positions C-5a
and C-6 induces a shift in the
position of the double bond between
the carbon atoms C-11 and C-11a
thereby forming the relatively more
energetically favoured resonant
system of the naphthalene group
found in the inactive
anhydrotetracyclines.
The strong bases on the other
hand promote a reaction
between the hydroxyl group at
C-6 and the carbonyl moiety at
C-11, thereby causing the bond
between C-11 and C-11a atoms
to cleave and eventually form
the lactone ring found in the
inactive isotetracyclines.
12. MAO :
• Tetracyclines enter bacteria by an active transport system
(absent in mammalian cell and resistant bacteria) and inhibit the
protein synthesis by preventing attachment of aminoacyl tRNA to the
acceptor site on the mRNA-ribosome complex.
• The binding of aminoacyl t-RNA and the binding of tetracyclines at
the ribosomal binding site both require magnesium ion.
13. Mechanism of Action
•Specific inhibitors of bacterial protein synthesis:Tetracyclines inhibit the protein synthesis of bacteria,
preventing their growth and replication by binding to the ribosomal subunit of bacteria, thereby impeding the
production of essential proteins.
15. Structural Activity Relationship of Tetracycline
1.Removal of one or more rings from the general structure of tetracycline abolish
the activity.
2.Ring D must be aromatic
3.Ring A must be appropriately substituted at C-1 =O, C-2 -CONH2, C-3 -OH, C-4
- N(CH3)2
4.Ring B & C can be tolerated some substitution at 5, 6 and 7- carbon atom.
16. 5.Following entities must be present for maximum activity:
at 3, 10, 12 carbon atom OH group.
at 2 carbon atoms CONH2 group.
at 1 and 11 carbon atoms =O group.
at 4 C. atom N(CH3)2 group (-oriented) (hydrogen atom at 4-carbon atom must be -oriented)
double bond between 2 & 3 and 11a & 12 carbon atom.
6.For Maximum activity fusion of ring A and B must be cis with alpha hydroxyl group at 12a carbon
atom
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-1 and C-3 results in loss of antibacterial activity A–C = O, a function of C-1 and C-3 is essential for
activity. In addition, equilibrium between non-ionized and Zwitterionic structure of tetracycline is
essential for activity.
17. 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 (Mannich bases).
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 antibacterial activity.
18. 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, and has been modified chemically to some semisynthetic tetracyclines.
Esterification is only acceptable if the free oxytetracycline can be liberated in vivo; only small
alkyl esters are useful. Epimerization is detrimental to antibacterial activity.
19. Modification at the C-6 position:
The C-6 methyl group contributes little to the activity of tetracycline. The C-6 position is
tolerant to a variety of substituents.
The majority of tetracyclines have α-methyl group and α β-hydroxyl group at this position
20. Demeclocyclin is a naturally occurring C-6 demethylated chlortetracycline with an
excellent activity.
Chlortetracycline
Demeclocyclin
21. Removal of C-6 hydroxyl group affords doxycycline, which exerts good antibacterial activity.
Doxycycline
22. C-7 and C-9 substituents:
The nature of the aromatic D-ring predisposes the C-7 position to electrophilic substitution.
Substitution with electron withdrawing group such as nitro and halogen groups are
introduced in some C-7 tetracyclines, which produces the most potent of all the tetracyclines in
vitro, but their are compounds are potentially toxic and carcinogenic. The C-7 acetoxy, azido, and
hydroxyl tetracyclines are inferior in terms of antibacterial activity.
10substituents: 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.
11substituents: The C-11 carbonyl moiety is a part of one of the conjugated keto-enol
system required for antibacterial activity.
23. C-11a substituents: No stable tetracyclines are formed by modifications at the C-11a position.
C-12/12a substituents: 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.
27. Spectrum of Activity
Range of Coverage
Tetracyclines have a
wide spectrum of
activity, making them
effective against various
pathogens, such as
respiratory, urinary,
and skin infections, as
well as rickettsial and
mycoplasma infections.
Limitations
While effective against
many bacteria,
tetracyclines have
limitations, particularly
in treating infections
caused by
Enterococcus faecalis
and Pseudomonas
aeruginosa.
Emerging Uses
Due to their broad
spectrum, tetracyclines
are now being explored
for potential applications
in the treatment of
conditions such as
periodontal diseases
and certain skin
disorders.
28. Therapeutic Uses of Tetracyclines
It is used in cholera, chlamydial infections, gonorrhoea, syphilis, acne, rickettsial infection,
brucellosis, shigellosis, amoebic dysentry, Whippler disease, Leptospirosis, Lyme disease,
Louse-borne & relapsing fever, nocardions, melioidosis, chronic bronchitis etc.
Adverse effects
Diarrhoea, oesophageal ulceration, temporary inhibition of long bone growth in infants,
nephrotoxicity, "fatty liver of pregnancy" in pregnant women,
superinfection of respiratoxy tract,
Jarisch- Herxheimer reaction,
photosensitivity
