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 an

d Chloramphenicol

Tetracycline Antibiotics

Tetracyclines are produced by actinomyces ( 放线菌 ),

which have broad-antibacterial spectrum. The basic s

keleton of tetracyclines is naphthacene ring. Tetracy

clines differing from each other chemically only by su

bstituent variation at positions 5,6 and 7.

R3 R2 R1 NOH

CONH2OOHO

OH

OH

HH

R4

123

45678

910 11 12

O

OOH

R3 R2

H

H R1

H

OH2N

OH

N

H

R4

OH

HO

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

ABCD

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

6-Methyl-4-(dimethylamino)-3,6,10,12,12a-

pentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2-

naphthacenecarboxamide

OH O

OH

H H

OH

OH

O

OH

CONH2

N(CH3)2

1

2

345

67

8

9

10 11 12

Stability under acid condition The tetracycline molecule, as well as those that contain the 6

β-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.

+N

OH

CONH2OH

OHHH

OH OO

H+ - H2O

- H+

OH NOH

CONH2OH

OHHH

OH O O

OH2+ N

OH

CONH2OH

OHHH

OH OO

NOH

CONH2

OHH

OH OH O O

ÍÑË®Îï

Formation of 4-Epitetracycline At C-4 in acidic medium (pH 2-6), epimerization of the “natura

l” 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.

OH NOH

CONH2OOHO

OHHH

OH

OHOH

CONH2OHOHO

OHHH

OH

H+N

OH

CONH2OHOHO

OHHH

OH

N

O

OH

CONH2OOHO

OHHH

OH

N

OH

4-Epitetracycline

Stability under base condition

In basic medium, ring C of tetracycline is opened to form isotetracycline.

OH-

OH NOH

CONH2OH

OHHH

OH OO

O- NOH

CONH2OH

OHH

OH OO

NOH

CONH2

OH

OH

O

O OO

HN

OH

CONH2O-

OH

OH

O

O O

HN

OH

CONH2O-O

OH

OH

O H

O

Formation of metal chelates

OH O

OH

H H

OH

OH

O

OH

CONH2

N(CH3)2Mn+

OH O

OH

H H

O

OH

O

OH

CONH2

N(CH3)2

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

Streptamine 2-Deoxystreptamine Spectinamine

( 链霉胺 ) (2- 脱氧链霉胺 ) ( 放线菌胺 )

NH NH2

NH

OH

OH

NH

H2NNH

HOHO

NH2

OH

H2N

HOHO

NHOH

HN

HOHO

HO

Chemistry

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.

（ L-Streptose ）

（ Streptide ）

（ N-Methyl-L-Glucosmine ）

NH NH2

NH

OH

OH

NH

H2NNH

OHO

ONHCH3

HO

HOH2C

HO

O

HO

OHC

OCH3

Caution ! It should be remember that penicillin and ami

noglycoside 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 a

s 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 syste

mic 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 nephroto

xicity. 18 of 21 actress showing “qianshou guanyin” were caused deaf

ness by aminoglycosides.

Streptomycin( 链霉素 )

Streptomycin is the first aminoglycosides isolated from

Streptomyces griseus.

There are three basic centers in the structure.

HOOH

HN NH2

NH

OHHN

H2NNH

OO

CHOO

HOHO

OHO

OHNHCH3

Clinical Use Streptomycin was the first aminoglycoside isolated a

nd 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 a

ntibiotics 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.

Erythromycin

A and B

A C-12=-OH

B C-12=-H

A and C

A C-3"=OCH3

C C-3"=-OH

O

OOH

HO

O

O O

N

HO

O

OHOMeO

HO

Erythromycin A

1

69

312

3"1"

1'3'

Cladinose

Desosamine

Erythronolide A

Extremely unstable under acid condition

O

O

OH

O

OHO

OO

OH

OHO

O

NOH

O

O

OHO

OO

OH

OHO

O

NOHO

O

O

OHO

OO

OHO

O

N

OO

HO

O

OO

HOO

N

OO

OH

OHO

OOH

+

1. H+

2. - H2O

ÍÑË®Îï8,9-Anhydroerythromycin A -6,9-hemiketal

ÂÝÐýͪAnhydroerythromycin A -6,9-9,12-spiroketal

¿ËÀ ¶¨ ÌÇCladinose

Simply modification of erythromycin-Ester Pro-drug

O

O

OH

O

OHO

OO

OH

ORO

O

NOH

ºì ùËØ̼ËáÒÒõ¥Ery thromy cin Ethy lcarbonate R = -COOCH2CH3ºì ùËØÓ²Ö¬Ëáõ¥Ery thromy cin Stearate R = -CO(CH2)16CH3çúÒÒºì ùËØEry thromy cin Ethy lsuccinate R = -CO(CH2)2OCOCH2CH3ÒÀÍкì ùËØEry thromy cin Estolate R = -COOCH2CH3, C12H25SO3H

Strategy for erythromycin modification

O

O

O

O O

O

HOOH

OHOMe

HO

NMe2

HO

OH

Alkylation of hydroxylgroup

Replacement of hydrogen

Conversion to aminesConversion to oximeRing expansion

Conversion to 11,12-cyclicderivatives

Cut Cladinoseto ketolides

°¢ÆëùËØ¡¡ Azithromycin

Dirithromycin

Erythromycin Oxime

ÂÞºì ùËØ¡¡ Roxithromycin

¼×»ù»¯»¹Ô

BeckmannRearraangement

O

N

OH

O

OHO

OO

OH

O HO O

N

O

OO

O

OH

O

OHO

OO

OH

OHO O

NOH

N

O

OH

O

OHO

OO

OH

OHO O

NOH

HN

O

OH

O

OHO

OO

OH

OHO O

NOH

HNO

O

N

OH

O

OHO

OO

OH

O HO O

NOH

O OO

O

O

OH

O

OHO

OO

OH

O HO O

NOH

O

N

OH

O

OHO

OO

OH

O HO O

NOH

OH

Erythromycin derivatives

O

OH

O

OHO

OO

OH

OHO

O

NOH

O F

O

O

O

OHO

OO

OH

OHO

O

NOH

O

·úºì ùËØFlunithromycin

¿ËÀ ùËØClarithromycin

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.

O

O

O

O ONOMe

HO

NMe2

O

O

O

N

N

N

Telithromycin

1

3

69

1112

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 gr

oup (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 strains

Chloramphenicol Antibiotics

Chloramphenicol ( 氯霉素 )

O2N

OH

H

H

HO

HN

Cl

Cl

HO

Chemical name:

D-(-)-threo-1-p-nitrophenyl-2-dichloroacetamido-

1,3-propanediol

A molecule, with two chiral centers, has four iso

mers (diastereomers). CHO

H OH

CH2OH

H OH

³àÞºÌÇD-(-)-erythrose

CHO

HO H

CH2OH

H OH

ËÕ°¢ÌÇD-(-)-threose

1R, 2R (-) 1S, 2S (+) 1S, 2R (+) 1R, 2S (+)

D-(-)-Threo ¡¡ ¡¡ ¡¡ ¡¡ L-(+)-Threo ¡¡ d-(+)-Erythro¡¡ ¡¡ ¡¡ ¡¡ ¡¡ ¡¡ L-(-)-Erythro

NO2

C1

C2

CH2OH

HHO

NHCOCHCl2H

NO2

C1

C2

CH2OH

OHH

HCl2CHCOHN

NO2

C1

C2

CH2OH

OHH

NHCOCHCl2H

NO2

C1

C2

CH2OH

HHO

HCl2CHCOHN

Chloramphenicol is an antibiotic produced by Streptomyce

s venezuelae and other soil bacteria that was first discover

ed 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

O2N

OH

H

H

OH

HN

OCl

Cl

HHN

OH

H

H

OH

NH

OCl

Cl

H

HO

OH

H

H

OH

NH

OCl

Cl

H

N

HOO

Zn, HCl

O

Cl

FeCl3

ôÇ°· ÑÜÉúÎïChloramphenicol Hydroxyamine

OH

H

H

OH

NH

OCl

Cl

H

N

HOO

3

Fe

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 β-lactam allergic patients, anaerobic( 厌氧菌 ) infection , rickettsial infections, and so on.

Synthesis O2N

O

Br2, C6H5ClO2N

O

(CH2)6N4, C6H5ClO2N

O

.(CH2)6N4

C2H5OH,HCl, H2OO2N

O

NH2.HCl

Br Br

Ac2O, AcONaO2N

O

NH

O

p-Nitro- -aminophenylacetone

HCHO, C2H5OH

pH = 2~7.5

O2N

O

NH

OHO

HAl[OCH(CH3)2]3, HOCH(CH3)2

O2N

NH

OHO

H

H OH

HCl, H2OO2N

NH2

HO

H

H OH

.HCl

15% NaOH O2N

NH2

HO

H

H OH

Resolution

O2N

OH

H OH

NH2H Cl2CHCOOCH3, CH3OH

O2N

OH

H OH

H HNCl

Cl

HO

p-Nitro- -acetamido- -hydroxyphenylpropanone ( )-thero-1-p-nitrophenyl-2-acetamidopropane-1,3-diol±

( )-thero-1-p-nitrophenyl-2-aminopropane-1,3-diol±

D-(-)-thero-1-p-nitrophenyl-2-aminopropane-1,3-diol

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 Palmitate ( 棕榈氯霉素 )

OH

H

H

O

NH

OCl

Cl

H

O

O2N

×ØéµÂÈùËØChloramphenicol Palmitate

C15H31-

 Chloramphenicol Sodium Succinate ( 琥珀氯霉素钠 )

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%.

OH

H

H

O

NH

OCl

Cl

H

OH

O

OO2N

çúçêÂÈùËØChloramphenicol Succinate

Na

Summary

Tetracyclines Aminoglycosides Macrolides

Erythromycin Structure modification of

semi-synthetic erythromycin

Chloramphenicol Mechanism of action

O

O

OH

O

OHO

OO

OH

OHO

O

NOH

OH

O2N

HOH

HHN

O

Cl

Cl

H

Question: 1. Why is the erythromycin A unstable in acidic co

ndition? 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