Transcript Tetracycline Antibiotics

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.
R4
H N
O 2
HO
R2 H
R1
R3
O
OH
H
H
O
OH H
R4 R3 R2 R1
8
7
9
D
10
N
6
CH
11
OH O
OH
5
BH
12
OH
N
4
OH
A
1
OH
3
2
CONH2
O
ÍÁùËØ£¨ Oxytetracycline£©
R1 = -OH
R2 = -OH
R3 = -CH3
R4 = -H
½ðùËØ£¨ Chlotetracycline£©
R1 = -H
R2 = -OH
R3 = -CH3
R4 = -Cl
ËÄ»· ËØ£¨ Tetracycline£©
R1 = -H
R2 = -OH
R3 = -CH3
R4 = -H
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.
Tetracycline
OH
7
6
8
H
N(CH3)2
5
4
H
OH
9
11
10
OH

O
1
12
OH
3
OH
2
CONH2
O
6-Methyl-4-(dimethylamino)-3,6,10,12,12apentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2naphthacenecarboxamide
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
anhydrotetracycline.
OH 2+
N
OH
OH
H
H
OH
H+
OH
N
H
H
CONH 2
OH O
CONH 2
OH O
OH
O
OH
O
N
+
H
N
OH
H
OH
OH
- H+
H
OH
CONH2
OH O
OH
O
- H2O
OH
CONH2
OH
OH O
O
ÍÑË®Îï
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.
H+N
OH
N
OH
OH
OH
H
OH
H
H
OH
H
CONH2
CONH2
OH O
OH
OH O
O
N
OH
OH
OH
N
OH
O
H
H
OH
OH
H
H
OH
CONH2
OH O
OH
OH
CONH2
OH O
OH
O
4-Epitetracycline
Stability under base condition

In basic medium, ring C of tetracycline is opened to
form isotetracycline.
O-
N
OH
OH
H
H
OH
N
OH
OH H
OH
CONH2
OH
O
OH
CONH2
O
OH
N
H
OH
OH
OH
OH
-O
O
O
OH
OH
O
N
H
OH
OH
O
CONH2
O
O O-
O
OH
OH
OH
O
CONH 2
N
O O
CONH2
O
Formation of metal chelates
OH
OH
H
H
OH
CONH2
OH O




OH
N(CH3)2
OH O
Mn+
N(CH3)2
OH
H
H
OH
CONH2
OH O
O
O
Mn+
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
H2N
NH
NH
H2N
OH
HO
HO
NH
OH
Streptamine
(链霉胺)
NH2
NH
HO
HO
HN
NH2
OH
HO
HO
HO
2-Deoxystreptamine
Spectinamine
(2-脱氧链霉胺)
(放线菌胺)
NH
OH
Chemistry
（N-Methyl-LGlucosmine）
HO
HOH2C
HO
H2N
NH
NHCH3
O
NH
O
HO
OHC
（Streptide）
OH
CH3O
O
HO
NH
OH
NH2
NH
（L-Streptose）

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.
Chemistry

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
sulfates.

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.
Toxicity


Their undesirable side effects: severe ototoxicity and
nephrotoxicity.
18 of 21 actress showing “qianshou guanyin” were caused
deafness by aminoglycosides.
Streptomycin(链霉素)
HO
HO
HO
O
NHCH3 OH H N
2
CHO
HN
O
O
O
HO
NH
OH
H
N
OH
NH2
NH
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
leprosy(麻风病).
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 14atom 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.
Erythromycin
N
HO
O
HO
Erythronolide A HO 12
3'
OH 1'
9
6
O O
3
O 1
O
O
O
1"
3"
Desosamine
Cladinose
OH
OMe
Erythromycin A
A and B
A C-12=-OH
B C-12=-H

A and C
A C-3"=OCH3
C C-3"=-OH
Extremely unstable under acid
condition
O
OH
OH
OH
OH
N
O
O
O
O
HO
1. H +
2. - H2O
O
OH
N
O
O
O
O
O
O
OH
O
HO
O
O
OH
O
ÍÑË®Îï
8,9-Anhydroerythromycin A -6,9-hemiketal
HO
O O
N
O
O
O
O
HO
OH
O
O
O
O
+
O O
ÂÝÐýͪ
Anhydroerythromycin A -6,9-9,12-spiroketal
N
O
OH
O
O
O
OH
HO
O
OH
¿ËÀ-¶¨ ÌÇ
Cladinose
Simply modification of erythromycin
-Ester Pro-drug
O
OH
OH
OH
N
O
O
O
O
RO
O
O
O
OH
ºì ùËØ̼ËáÒÒ
õ¥
Ery thromy cin Ethy lcarbonate
ºì ùËØÓ²Ö¬Ëáõ¥
Ery thromy cin Stearate
çúÒÒ
ºì ùËØ
Ery thromy cin Ethy lsuccinate
ÒÀÍкì ùËØ
Ery thromy cin Estolate
R = -COOCH2CH 3
R = -CO(CH2)16CH3
R = -CO(CH2)2OCOCH2CH 3
R = -COOCH2CH 3, C12H25SO3H
Strategy for erythromycin
modification
Replacement
of hydrogen
Conversion to amines
Conversion to oxime
Ring expansion
Alkylation of
hydroxylgroup
H
O
NMe2
HO
OH
HO
Conversion to
11,12-cyclic
derivatives
O
O
HO
O
O
O
O
OH
OMe
Cut Cladinose
to ketolides
O
N
OH
OH
OH
OH
N
O
O HO
O
O
O
O
OH
OH
O
N
O
O
O HO
O
OH
O
O
N
O
OH
O
O
OH
O
ÂÞºì ùËØ¡¡ Roxithromycin
OH
OH
O
OH
O
O
O HO
O
O
HN
OH
OH
O
O HO
O
OH O
O
N
OH
O HO
O
O
O
O
Erythromycin Oxime
O
OH
O
Dirithromycin
O
O
OH
O
O
N
O
N
O
Beckmann
Rearraangement
OH
O
N
N
OH
HN
OH
OH
OH
OH
OH
»¹ Ô-
N
O
O
OH
O HO
O
O
N
O
¼×»ù»¯
O
O HO
O
O
O
O
O
OH
O
OH
°¢Æë
ùËØ¡¡ Azithromycin
Erythromycin derivatives
O F
OH
O
OH
OH
OH
OH
N
O
O
O
O
HO
O
O
O
O
O
O
·ú ºì ùËØ
Flunithromycin
N
OH
O
O
HO
O
O
O
¿ËÀ-ùËØ
Clarithromycin
OH
Telithromycin

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.
N
N
N
NMe2
HO
O
O
N
O
OMe
9
6
11
12
O
3
O 1
O
O
Telithromycin
O

In addition to the C-3 ketone,
telithromycin has an aromatic Nsubstituted 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 3keto function and giving the ketolide
molecule excellent acid stability.

The ketolides are very active
against respiratory pathogens,
including erythromycin-resistant
strains
Chloramphenicol
Antibiotics
Chloramphenicol (氯霉素 )
O
H
O2N
Cl
H
HN
Cl
OH
HO
H

Chemical name:

D-(-)-threo-1-p-nitrophenyl-2-dichloroacetamido1,3-propanediol
A molecule, with two chiral centers, has four
isomers (diastereomers).
CHO
H
OH
H
OH
CH2OH
CHO
HO
H
H
OH
CH2OH
³àÞºÌÇ
D-(-)-erythrose
ËÕ°¢ÌÇ
D-(-)-threose
NO2
HO
H
C
1
C
2
NO2
H
H
NHCOCHCl2
Cl2CHCOHN
CH2OH
1
C
2
OH
H
CH 2OH
1R, 2R (-)
D-(-)-Threo
C
NO2
1S, 2S (+)
¡¡ ¡¡ ¡¡ ¡¡
L-(+)-Threo
H
H
C
1
C
2
NO2
OH
HO
NHCOCHCl2
Cl2CHCOHN
CH2OH
1
C
2
H
H
CH2OH
1S, 2R (+)
¡¡ d-(+)-Erythro¡¡
C
1R, 2S (+)
¡¡ ¡¡ ¡¡ ¡¡ ¡¡
L-(-)-Erythro
Chloramphenicol is an antibiotic produced by
Streptomyces venezuelae and other soil bacteria that was
first discovered in 1947 and is now exclusively produced
synthetically.
With two chiral centers it is one of four diastereomers only one of
which (1R, 2R) is active.
Chemical properties
O
O2N
H
H
O
Cl
HN
Zn, HCl
Cl
HO
H
N
H
Cl
Cl
OH
H
OH
ôÇ°· ÑÜÉúÎï
Chloramphenicol Hydroxyamine
OH
O
N
O
O
Cl
NH
OH
H
H
H
HO
O
Cl
NH
N
Cl
OH
H
H
OH
FeCl3
O
H
HO
H
Cl
NH
Cl
Fe
OH
H
OH
3
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.
Usage
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 βlactam allergic patients, anaerobic(厌氧菌)
infection , rickettsial infections, and so on.
Synthesis
O2N
O2N
Br2, C6H5Cl
(CH2)6N4, C6H5Cl
O2N
Br .(CH2)6N4
Br
O
O
C2H5OH,HCl, H2O
O2N
O
Ac2O, AcONa
O2N
O
N
H
NH2.HCl
O
O
p-Nitro- -aminophenylacetone
HCHO, C2H5OH
O
H
Al[OCH(CH3)2]3, HOCH(CH3)2
H OH
(±)-thero-1-p-nitrophenyl-2acetamidopropane-1,3-diol
O
p-Nitro- -acetamido--hydroxyphenylpropanone
HO
O2N
HCl, H2O
15% NaOH
HO
O2N
H
NH2
H OH
H OH
(±)-thero-1-p-nitrophenyl-2aminopropane-1,3-diol
O
H
NH2
OH
H OH
D-(-)-thero-1-p-nitrophenyl2-aminopropane-1,3-diol
Resolution
H
NH2 .HCl
O2N
O
H
N
H
N
H
pH = 2~7.5
HO
O2N
HO
O2N
Cl2CHCOOCH3, CH3OH
O2N
H HN
OH
H OH
H
Cl
Cl
Chloramphenicol Palmitate (棕榈氯霉素)
O
O2N
H
H
Cl
NH
Cl
O
H
OH
O
-C15H31
×ØéµÂÈùËØ
Chloramphenicol Palmitate
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
form.
Chloramphenicol Sodium Succinate
(琥珀氯霉素钠)
O
H
O2 N
H
Cl
NH
Cl
O
H
Na
OH
O
OH
O
çúçêÂÈùËØ
Chloramphenicol Succinate
Chloramphenicol sodium succinate is the watersoluble 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%.
Summary



Tetracyclines
Aminoglycosides
Macrolides




O
OH
OH
OH
N
O
O
O
O
Erythromycin
Structure modification of
semi-synthetic
erythromycin
Chloramphenicol
Mechanism of action
HO
O
O
OH
O
O
O2 N
H
HO
HN
H
H
Cl
Cl
OH

Question:



1. Why is the erythromycin A unstable in acidic
condition?
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