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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 (), 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.
H N O 2 HO R2 H R1 H O OH Oxytetracycline Chlotetracycline Tetracycline R1 = -OH R1 = -H R1 = -H H OH H N O OH
8 9
R4
R3
R4 R3 R2 R1
7
N
4
D
10
CH
11
BH
12
OH
3 2
OH A
1
CONH2
OH O
OH
R4 = -H R4 = -Cl R4 = -H
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 () cells do not have a tetracycline uptake mechanism.
Tetracycline
7 8
H OH N(CH3)2
4
OH
3 2
OH
9 10
OH O
11
OH
12
O
CONH2
6-Methyl-4-(dimethylamino)-3,6,10,12,12apentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2naphthacenecarboxamide
The tetracycline molecule, as well as those that contain the 6-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 H OH O H
N OH OH CONH2 OH O N
+
OH2+ H+ H OH O H OH
N OH OH CONH2 O N - H2O
OH H OH OH CONH2 O
H OH O
- H+
OH H OH OH O OH CONH2 O
Formation of 4-Epitetracycline
At C-4 in acidic medium (pH 2-6), epimerization of the natural C-4 -dimethylamino group to the C-4-epimer occurs. Under acidic conditions, a 1:2 equilibrium is established in solution within a day.
H+N OH H CONH 2 OH O OH O OH H OH O H OH N O OH CONH 2 OH OH O OH O 4-Epitetracycline H H OH CONH 2 OH O OH OH OH N OH H OH CONH 2
OH H H
N OH OH
OH
N OH OH CONH 2 O H O OH O O N OH OH CONH2 O
OH O O
OH H O Mn+
N(CH3)2 OH OH CONH2 O
OH O
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
Streptamine ()
2-Deoxystreptamine (2-)
Spectinamine ()
Chemistry
N-Methyl-LGlucosmine
HO HOH2C HO O NHCH3 NH CH3O HO OHC O O HO OH NH OH H2N NH
Streptide
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 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 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()
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, plague and leprosy(). 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 (
Erythromycin is an orally effective antibiotic discovered in 1952 in the metabolic products of a strain of Streptomyces eryyhreus(), 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 O HO 3' OH 1' 9 6 O O 3 O O 1" 3" HO
Desosamine
Erythronolide A HO 12
O 1 O
Cladinose
OH OMe
Erythromycin A
O OH N O HO O OH O
O HO O O
Anhydroerythromycin A -6,9-9,12-spiroketal
H O HO
Conversion to 11,12-cyclic derivatives
NMe2 HO OH O O O OH OMe
Cut Cladinose to ketolides
HO O O
O OH OH O O O O HO O O OH N OH OH O O HN OH OH O O O O HO O O OH HN OH O OH O O O HO O O OH N O OH Beckmann Rearraangement N O O O HO O O OH O O OH N
N OH OH O
O OH
N O HO O O O OH O
Roxithromycin OH N OH O O O OH O O OH N O HO O OH O O O N
Azithromycin
Erythromycin derivatives
O F OH OH O O O O HO O OH O O OH N O O OH OH O HO O OH O O O N
O Flunithromycin
O - Clarithromycin
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 O O N O 9 11 12 6 3 O HO OMe O O
O 1 O
Telithromycin
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 ( )
O O2 N H HN Cl OH H Cl
HO
Chemical name:
D-(-)-threo-1-p-nitrophenyl-2-dichloroacetamido1,3-propanediol
NO2
NO2
NO2
NO2
HO H
1 2
H NHCOCHCl2
H Cl2CHCOHN
1 2
OH H
H H
1 2
OH NHCOCHCl2
HO Cl2CHCOHN
1 2
H H
CH2OH
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 HN Cl OH OH H H O Cl Zn, HCl HO H N H NH Cl OH OH Chloramphenicol Hydroxyamine O N O HO H H NH Cl OH OH FeCl3 O HO H H O Cl N H NH Cl OH OH 3 H H
O
Cl
Cl
Cl
Fe
Usage
Despite potentially serious limitations, Chloramphenicol is an excellent drug when used carefully. Its special value is in typhoid () and paratyphoid fever , Haemophilus infection , pneumococcal () and meningococcal meningitis() in lactam allergic patients, anaerobic() infection , rickettsial infections, and so on.
Synthesis
O2N
O2N Br O
(CH2)6N4, C6H5Cl
O2N Br .(CH2)6N4 O
C2H5OH,HCl, H2O
O2N N H O
O p-Nitro- -aminophenylacetone
O2N
HO H N H O
HO H N H O
O p-Nitro- -acetamido--hydroxyphenylpropanone
H OH ()-thero-1-p-nitrophenyl-2acetamidopropane-1,3-diol
HO H NH2 .HCl H OH
15% NaOH
O2N
HO H NH2
Resolution
H OH ()-thero-1-p-nitrophenyl-2aminopropane-1,3-diol O O2N H Cl Cl
O2N
NH2 OH H OH D-(-)-thero-1-p-nitrophenyl2-aminopropane-1,3-diol
Cl2CHCOOCH3, CH3OH
H HN OH H OH
Chloramphenicol Palmitate ()
O O2N H H NH Cl O OH O
-C15H31
Cl
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 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
O OH OH O O O O HO O O O OH OH N
O H HN
Cl
Cl OH
HO
Question:
1. Why is the erythromycin A unstable in acidic condition? 2. What is the difference of the action mechanism of antibiotics? 1.Read textbook pp334-355,360-361 2.Do homework Exercises of medicinal chemistry p96 Type A and,
Assignment: