Tetracycline
Contents
• Tetracyclines – Introduction
• Structure and chemistry of Tetracyclines
• Mechanism of Action of Tetracyclines
• Spectrum of activity
• Structure and Activity Relationship of Tetracyclines
• Study of individual compounds
Learning Objectives
At the end of this
lecture, student will be able to
• Explain the structure and chemistry of Tetracyclines
• Discuss the mode of action of Tetracyclines
• Explain about the spectrum of activity
• Compare the structure with the activity of Tetracyclines
• Differentiate the structural features of individual
compounds
TETRACYCLINES
• Most important broad-spectrum antibiotics.
• Nine compounds in this family are in medicinal use.
• Tetracycline
• Rolitetracycline
• Oxytetracycline
• Chlortetracycline
• Demeclocycline
• Meclocycline
• Methacycline
• Doxycycine
• Minocycline
Introduction
• Obtained by fermentation procedures from Streptomyces
spp., by chemical transformation of natural products.
• The important members of the group are derivatives of an
Octahydronaphthacene, a hydrocarbon system that comprises of four annulated six
– membered rings
• The group name is derived from the tetracyclic system
• The antibiotic spectra and chemical properties of these
compounds are very similar but not identical.
Chemistry
• Structure and chemistry of Tetracyclines:
• Tetracyclines are amphoteric compounds, forming salts with
either acids or bases. In neutral solutions, these substances exist mainly as zwitter
ions
• Acid salts are formed through protonation of the enol
group on C-2
|
Tetracycline Analog |
R1 |
R2 |
R3 |
R4 |
|
Tetracycline |
H |
CH3 |
OH |
H |
|
Chlortetracycline |
Cl |
CH3 |
OH |
H |
|
Oxytetracycline |
H |
CH3 |
OH |
OH |
|
Demeclocycline |
Cl |
H |
OH |
H |
|
Methacycline |
H |
CH3 |
– |
OH |
|
Meclocycline |
Cl |
CH3 |
– |
OH |
|
Doxycycline |
H |
H |
CH3 |
OH |
|
Minocycline |
N(CH3)2 |
H |
H |
H |
• ‘The unusual structural groupings in the tetracyclines
produce three acidity constants in aqueous solutions of acid salts for eg.,
|
Tetracycline Analog |
pKa1 |
pKa2 |
pKa3 |
|
Tetracycline |
3.3 |
7.7 |
9.5 |
|
Chlortetracycline |
3.3 |
7.4 |
9.3 |
• The groups are as shown below,
Tetracyclines have the ability to undergo epimerization at
C-4 in solutions of intermediate pH. These isomers are called ‘epitetracyclines’
Under acidic conditions, an equilibrium is established in
about 1day and consists of approximately equal amounts of the isomers
These ‘4-epitetracyclines’ exhibit much less activity than
the ‘natural’ isomers, thus accounting for the decreased therapeutic value of
aged solutions
Epitetracycline Tetracycline
• Strong acids and strong bases attack tetracyclines with a
hydroxyl groups on C-6, causing a loss in activity through modification of the
C-ring.
• Strong acid produce dehydration through a reaction
involving the 6- hydroxyl group and the 5a-hydrogen.
• The double bond thus formed between positions 5a and 6
induces a shift in the position of the double bond between C-11a and C-12 to a
position between C-11 and C-11a, forming the more energetically favored
resonance system of the naphthalene group found in the inactive
ANHYDROTETRACYCLINES
• Bases promote a reaction between 6-hydroxy group and the
ketone group at the 11 position, causing the bond between the 11 and 11a atoms
to cleave, forming the lactone ring found in the inactive isotetracycline.
• These unfavourable reactions led to the development of
more stable and longer-acting compounds as 6-deoxytetracyclines, methacycline,
doxycycline and minocycline.
• Stable chelate complexes
are formed by
the tetracyclines with many
metals including calcium,
magnesium and iron – such chelates are usually very insoluble in
water causing impaired absorption of most of the tetracyclines in presence of
milk, calcium, magnesium and aluminum containing antacids and iron salts.
• Soluble alkalinizers such as sodium bicarbonate also
decreases the GI absorption of the tetracyclines.
• Deposition of these
antibiotics in teeth
cause a yellow discoloration that darkens (photochemical
reaction) over time.
• Tetracyclines are distributed into the milk of lactating
mothers and will cross the placental barrier into the fetus.
• Tetracyclines has affinity for calcium causing them to be
incorporated into newly forming bones and teeth as tetracycline – calcium
orthophosphate complexes.
• The possible effects of these agents on the bones and
teeth of the child should be considered before their use during pregnancy or in
children under 8 years of age.
• The stereochemistry of the tetracyclines is very complex. Carbon
atoms 4, 4a, 5, 5a, 6 and 12a are potentially chiral depending on the
substitution. Oxytetracycline and doxycycline each with a 5α- hydroxyl
substituent has six asymmetric centers. Others that lack chirality at C-5 have
only five asymmetric centers.
• Conjugated systems exist in the structure from C-10
through C-12 and from C-1 to C-3 (in one canonical form)
Mechanism
of Action
• Tetracyclines are specific inhibitors of bacterial protein
synthesis.
• They bind to the 30S ribosomal subunit and thereby prevent
the binding of aminoacyl tRNA to the mRNA – ribosome complex.
• Both the bindings- of aminoacyl tRNA and the binding of
tetracyclines at the binding site- require magnesium ions
• Tetracyclines remove essential metal ions (like Mg) as
chelated compounds.
• Tetracyclines also bind to mammalian ribosomes but with
lower affinities and do not achieve sufficient intracellular, concentrations to
interfere with the protein synthesis
• The selective toxicity of the tetracyclines towards
bacteria depends strongly on the self-destructive capacity of bacterial cells
to concentrate these agents in the cell.
• Tetracyclines enter the bacterial cells by two processes:
a. Passive diffusion and b. active transport.
Spectrum of
Activity
• Tetracyclines have the broadest spectrum of activity of any
known anti-bacterial agents
• They are active against a wide range of Gram +ve and
Gram-Ve bacteria, Spirochetes, Mycoplasma, Rickettsiae and Chlamydiae.
• They are bacteriostatic and
so they are
not effective in the
treatment of life threatening infections such as septicemia, endocarditis and
meningitis.
• Parenteral tetracyclines may cause severe liver damage,
especially when given in excessive dosage to pregnant women or to patients with
impaired renal function.
STRUCTURE –
ACTIVITY RELATIONSHIPS
• All derivatives containing fewer than four rings are
inactive.
• Many of the structural features present in this molecule
must remain unmodified for derivatives to retain activity.
• The substituents at carbon atoms 1, 2, 3, 4, 10, 11, 11a
and 12 representing the hydrophilic faces of the molecule cannot be modified
drastically, without deleterious effects on the anti- microbial properties of
the resulting derivatives.
A-ring:
• A-ring substituents can be modified only slightly without
drastic loss of anti-bacterial potency.
• The enolized tricarbonyl methane system at C-1 and C-3 must
be intact for good activity.
• Replacement of
the amide at C-2 with
other functions (eg., aldehyde or nitrile) reduces or
abolishes activity.
• Mono-alkyation of the amide nitrogen reduces activity
proportionately to the size of the alkyl group
• Aminoalkylation of the amide nitrogen by mannich reaction,
yields derivatives that are more water soluble than the parent tetracycline and
are hydrolyzed to it in-vivo (eg., Rolitetracycline)
• The dimethylamino group at the 4th position must have the
α- orientation.
• 4-epitetracyclines are very much less active than the
natural isomers.
• Removal of the 4-dimethylamino group reduces activity even
further.
• Activity is largely retained in the primary and N-methyl
secondary amines but rapidly diminishes with higher alkylamines.
Ring B
• A cis-A/B ring fusion with a β-hydroxy group at C-12a is
essential.
• Esters of the C-12a hydroxyl group are inactive, with the
exception of the formyl ester, which readily hydrolysis in aqueous solutions.
• Alkylation at C-11a leads to inactive compounds- therefore
an enolizable β-diketone is important at C-11 and C-12.
• Epimerization at C-5a causes loss of antibacterial
potency.
• Dehydrogenation to form a double bond between C-5a and
C-11a markedly decreases antibacterial activity
• Substituents at positions 5, 5a, 6, 7, 8 and 9 are
hydrophobic faces of the molecule – can be modified resulting in retention and
sometimes improvement of antibiotic activity.
• 5-OH group in oxytetracycline and doxycycline influence
pharmacokinetic properties but does not change anti-microbial activity.
Ring C
• Aromitization of ring C decreases activity
(Anhydrotetracyclines)
• Neither the 6α-methyl nor the 6β-hydroxyl group is essential
for antibacterial activity.
• In fact doxycycline and methacycline are more active
in-vitro than the parent oxytetracycline.
• 6-epidoxycycline is much less active than doxycycline.
Advantages of
6-deoxytetracyclines
• They cannot form inactive anhydrotetracyclines in acidic
conditions as they cannot dehydrate at C-5a & C-6.
• They are more stable in base because they do not undergo
β-ketone cleavage followed by Lactonization to form isotetracyclines.
• Absorbed more completely following oral administration,
have higher fractions of protein binding, higher volumes of distribution and
lower renal clearance.
Ring D
• Acid stable 6-deoxytetracyclines & 6-demethyl-6-deoxytetracyclines
are used to prepare a variety of mono- and di- substituted derivatives by
electrophilic substitution reactions at C-7 and C-9 of D-ring
• Introduction of strong electron-withdrawing groups
especially at C-7 (eg., chloro and nitro –Chlortetracycline) enhances activity.
• Strong electron donating groups (eg., dimethyl
amino-Minocycline) enhance the activity.
• C-8 cannot be directly substituted by electrophilic aromatic
substitution
Tetracycline
• Isolated from fermentation of Streptomyces species
• Chem.name:
4-Dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacene
carboxamide.
Use:-
• Used as ointments for topical and ophthalmic
administration
• A topical solution is used for the management of acne
vulgaris..
Chlortetracycline
• Isolated from S. aureofaciens.
• Valuable antibiotic with broad spectrum activities.
• Chem. Name:-
7-chloro-4-Dimethyl amino- 1,4,4a,5,5a,6,11,12a-
octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacene
carboxamide.
Use:-
• Used as ointments for topical and ophthalmic
administration
Oxytetracycline
• Isolated from S.rimosus.
• Absorbed well orally
• Also used for parenteral administration (intravenously
& intramuscularly)
Doxycycline
Doxycycline (monohydrate):- Α-6-deoxy-5-oxytetracycline
• 6α-methyl epimer is more than 3 times as active as its
β-epimer.
• Unlike other tetracyclines, it does not accumulate in
patients with impaired renal function. Therefore, it is preferred for UREMIC
patients with infections outside the urinary tract.
• Very well absorbed from the GIT- hence smaller dose maybe
used
Minocycline
• Chem. Name:- 7-dimethylamino-6-dimethyl-6-demethyl-6-deoxy
tetracycline.
• Most potent tetracycline.
• Well absorbed orally
• Has very long serum half-life due to slow urinary
excretion & moderate protein binding
• Active against Gram +ve bacteria especially Staphylococci
and Streptococci
• Useful alternative for the treatment of less serious
tissue infections
• Recommended for the treatment of chronic bronchitis and
other upper respiratory tract infections
• Used for the treatment of urinary tract infections
• It is effective in the eradication of N. meningitides in
asymptomatic carriers.