Tetracycline Antibiotics

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					Chapter 8 Antibiotics

Section   2. Tetracyclines
Section   3. Aminoglycoside
Section   4. Macrolides
Section   5. Chloramphenicol
Antibiotics as disturber with the
biosynthesis 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 Tetracyclines
       Inhibitors of the 50s Ribosomal subunit: Macrolides
        and Chloramphenicol
Tetracycline Antibiotics
Tetracyclines are produced by actinomyces (放线菌),
which have broad-antibacterial spectrum. The basic
skeleton of tetracyclines is naphthacene ring.
Tetracyclines differing from each other chemically
only by substituent variation at positions 5,6 and 7.
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.
Mechanism of Action:
  Tetracyclines inhibit bacterial protein synthesis by
blocking the attachment of the t-RNA-amino acid to
the ribosome.
    Tetracyclines can also inhibit protein synthesis in
the host, but are less likely to reach the concentration
required because eukaryotic (真核状态的) cells do not
have a tetracycline uptake mechanism.

   6-Methyl-4-(dimethylamino)-3,6,10,12,12a-
Stability under acid condition
   The tetracycline molecule, as well as those that contain the
    6β-hydroxy group, is labile to acid and base degradation. At
    pH 2.0, tetracycline eliminates a molecule of water with
    concomitant aromatization of ring C to form
Formation of 4-Epitetracycline
   At C-4 in acidic medium (pH 2-6), epimerization of the “natural”
    C-4 α-dimethylamino group to the C-4β-epimer occurs. Under
    acidic conditions, a 1:2 equilibrium is established in solution
    within a day.
Stability under base condition
   In basic medium, ring C of tetracycline is opened to
    form isotetracycline.
    Formation of metal chelates

   Stable chelate complexes are formed by the tetracyclines with many
    metals, including calcium, magnesium, and iron. Such chelates are
    usually very insoluble in water.
   The affinity of tetracyclines for calcium causes them to incorporated
    into newly forming bones and teeth as tetracycline-calcium
    orthophosphated complexes. Deposits of these antibiotics in teeth
    cause a yellow discoloration.
   The tetracyclines are distributed into the milk of lactating mothers and
    will cross the placental barrier into the fetus.
   The possible effects of these agents on bones and teeth of the child
    should be considered before their use during pregnancy or in children
    under 8 years of age.
Aminoglycoside Antibiotics
The aminoglycoside class of antibiotics contains
a pharmacophoric 1,3-diaminoinositol (1,3-二氨
基肌醇) derivatives

 Streptamine       2-Deoxystreptamine    Spectinamine
 (链霉胺)              (2-脱氧链霉胺)             (放线菌胺)



    Aminoglycosides are so named because their
     structures consist of amino sugars linked
     glycosidically. All have at least one aminohexose,
     and some have a pentose lacking an amino group.
Caution !
   It should be remember that penicillin and
    aminoglycoside antibiotics must never be
    physically mixted, because both are
    chemically inactivated to a significant degree
    on mixting.
   Aminoglycosides are strong basic compounds that exist
    as polycations at physiological pH. Their inorganic acid
    salts are very soluble in water. All are available as
   The high water solubility of the aminoglycosides no
    doubt contributes to their pharmacokinetic properties.
    They distribute well into most body fluids but not into
    the ventral nervous system, bone, or fatty or connective
    tissues. They tend to concentrate in the kidneys and
    excreted by glomerular filtration. Aminoglycosides are
    apparently not metabolized in vivo.
Spectrum of activity
   Aminoglycosides are used for treatment of serious
    systemic infections caused by aerobic Gram-negative
    bacilli. Aerobic G-N and G-P cocci tend to be less
    sensitive; thus the β–lactams and other antibiotics tend
    to be preferred for the treatment of infections caused by
    these organisms. Anaerobic bacteria are invariably
    resistant to the aminoglycosides.
   Streptomycin is the most effective of the group for the
    chemotherapy of tuberculosis.
   Under certain circumstances, aminoglycoside and β–
    lactams antibiotics exert a synergistic action in vivo
    against some bacterial strains when the two are
    administered jointly.
Mechanism of Action
   The mechanism of action of these antibiotics
    believed that they can inhibit the biosynthesis of
    protein of bacteria.
   At less than toxic doses, they bind to the protein
    portion of the 30S ribosomal subunit leading to
    mistranslation of RNA templates and the
    consequent insertion and wrong amino acids
    and formation so-called nonsense proteins.
   Their undesirable side effects: severe ototoxicity and
   18 of 21 actress showing “qianshou guanyin” were caused
    deafness by aminoglycosides.

  Streptomycin is the first aminoglycosides isolated from
Streptomyces griseus.
  There are three basic centers in the structure.
Clinical Use
   Streptomycin was the first aminoglycoside isolated
    and the first antibiotic with potent activity against
    Mycobacterium tuberculosis and this antibiotic
    continues to be used to treat tuberculosis, but as a
    result of the development of resistance, now in
    combination therapy with other antibiotics.
   Streptomycin can also be used for the treatment of
    tularemia(野兔病), plague(瘟疫) and
   The aminoglycosides are highly water soluble and
    poorly absorbed orally. These antibiotics are
    therefore primarily delivered by intramuscular
    injection or intravenously.
Macrolide Antibiotics
Macrolide Antibiotics
   Naturally occurring macrolide
    antibiotics are grouped into
    three major groups of 12-, 14-,
    and 16-membered macrolides
    with the aglycone consisting of
    12-, 14-, and 16-atom cyclic
    lactone rings, respectively. For
    example, erythromycin A is a
    14-membered macrolide (a 14-
    atom cyclic lactone ring) and
    possesses desosamine and
    cladinose glycosidically linked
    to C-5 and C-3, respectively.
Mechanism of action

   The mechanism of action of macrolides is
    that: it inhibits bacteria by interfering with
    programmed ribosomal protein
    biosynthesis by inhibiting translocation of
    amino acid m-RNA following binding to
    the 50s subunit.
Erythromycin (红霉素)

   Erythromycin is an orally effective antibiotic
    discovered in 1952 in the metabolic products of
    a strain of Streptomyces eryyhreus(红色链丝菌),
    it includes Erythromycin A, B, and C. The
    component A is used in clinic primarily.
   It is active for most G-P and some G-N.

    A and B    A and C
   A C-12=-OH   A C-3"=OCH3
   B C-12=-H    C C-3"=-OH
Extremely unstable under acid
Simply modification of erythromycin
-Ester Pro-drug
Strategy for erythromycin
Erythromycin derivatives
   Telithromycin is the first
    ketolide(3-keto macrolide
    derivatives). It is
    prepared by removing the
    cladinose sugar from the
    C-3 position of the
    erythronolide skeleton
    and oxidizing the
    remaining hydroxyl group
    to a keto group.
   In addition to the C-3 ketone,
    telithromycin has an aromatic N-
    substituted carbamate extension at
    position C-11 and C-12. This ring has
    an imidazo-pyridyl group attachment.
   Telithromycin possesses a 6-OCH3
    group (like clarithromycin), avoiding
    internal kemiketalization with the 3-
    keto function and giving the ketolide
    molecule excellent acid stability.
   The ketolides are very active
    against respiratory pathogens,
    including erythromycin-resistant
Chloramphenicol (氯霉素 )

   Chemical name:
   D-(-)-threo-1-p-nitrophenyl-2-dichloroacetamido-
A molecule, with two chiral centers, has four
isomers (diastereomers).
Chloramphenicol is an antibiotic produced by
Streptomyces venezuelae and other soil bacteria that was
first discovered in 1947 and is now exclusively produced

With two chiral centers it is one of four diastereomers only one of
which (1R, 2R) is active.
Chemical properties
Chloramphenicol is bacteriostatic by inhibition of
protein biosynthesis.
Its toxicities prevent Chloramphenicol from being
more widely used.
The major adverse effect of chloramphenicol is
a risk of fatal irreversible aplastic anemia that
occurs after therapy and does not appear to be
related to dose or administration route.
Reversible bone marrow suppression and
several other adverse effects including
gastrointestinal problems, headache, and mild
depression have also been noted.
  Despite potentially serious limitations,
 Chloramphenicol is an excellent drug
 when used carefully. Its special value is in
 typhoid (伤寒) and paratyphoid fever(副
 伤寒), Haemophilus infection ,
 pneumococcal (肺炎球菌) and
 meningococcal meningitis(脑膜炎) in β-
 lactam allergic patients, anaerobic(厌氧菌)
 infection , rickettsial infections, and so on.
Chloramphenicol Palmitate (棕榈氯霉素)

Chloramphenicol Palmitate is the palmitic acid
ester of chloramphenicol. It is a tasteless
prodrug of chloramphenicol intended for
pediatric use. The ester must hydrolyze in vivo
following oral absorption to provide the active
 Chloramphenicol Sodium Succinate

  Chloramphenicol sodium succinate is the water-
soluble sodium salt of the hemisuccinate ester of
chloramphenicol. Because of the low solubility of
chloramphenicol, the sodium succinate is preferred
for intravenous administration. The availability of
chloramphenicol from the ester following intravenous
administration is estimated to be 70 to 75%.
   Tetracyclines
   Aminoglycosides
   Macrolides
       Erythromycin
       Structure modification of
   Chloramphenicol
   Mechanism of action
   Question:
       1. Why is the erythromycin A unstable in acidic
       2. What is the difference of the action mechanism
        of antibiotics?
   Assignment:
       1.Read textbook pp334-355,360-361
       2.Do homework Exercises of medicinal chemistry
        p96 Type A and药物化学学习指导,第八章