Wilson and Gisvold’ s Textbook of Organic Medicinal and Pharmaceutical Chemistry Chapter 8 Page 308 Macrolides They are antibiotics produced by Streptomyces species Chemistry They contain macrocyclic lactone ring (highly substituted monocyclic lactone named aglycone), to which; one or more deoxy sugars, usually cladinose (neutral sugar) and desosamine (amino sugar ) are attached at 3 & 5, and a ketone group. This aglycone ring ranges in size from 12, 14 or 16 membered rings. O OH 12 13 10 9 11 OH 7 OH 14 4 1 3 O O 8 2 6 5 desosamine cladinose Erythromycin (1952) To overcome the problems of bitterness and irregular oral absorption, some modifications were applied (Prodrugs): 1. Formation of acid salt of the basic dimethyl amino group of the aminosugar, desosamine such as the glucoheptonate and lactobionate (injection) the stearate and N-lauryl sulfate salt (oral) . 2. Formation of esters of 2’ OH gp of the desosamine sugar as ethyl succinate which is hydrolysed in the intestine, propionate which are hydrolysed by plasma and tissue esterase. Erythromycin estolate (oral) is C2`propionyl ester, N-Lauryl sulphate salt. Instability of erythromycin In acidic media a facile intra-molecular cyclization in which the hydroxyl group at C6 adds to the carbonyl gp at C9, forming a 6,9-hemiketal that undergoes irreversible dehydration (between 8&9) Participation of the hydroxyl group at C12 in a second intramolecular cyclization yields the 6,9, 9, 12 spiroketal, either through the intermediate anhydrohemiketal or directly from erythromycin. Irreversible Irreversible Semisynthetic derivatives to prevent the intramolecular reactions. 1. Roxithromycin is an example for the conversion of the ketonic group into oxime. (Methoxyethoxymethoxyimino) 2. Azithromycin is a modification, 9oxime gave ring expansion to a 15membered intermediate, in which a basic nitrogen atom was embedded into the aglycone 3. Clarithromycin 6-methyl ether of Erythromycin with marked reduced GI side effects with markedly increased acid stability Mode of action (bacteriostatic): They selectively bind to a specific site on the 50S ribosomal subunit to prevent the translocation step of bacterial protein synthesis. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection. Bacterial Spectrum (resembles that of penicillins) They are effective against most gram +ve bacteria and some gram –ve bacteria. Also effective against Mycoplasma, Chlamydia and Legionella. Often used to treat upper and lower respiratory tract infections, and some sexually transmitted diseases caused by mixed infections. Wilson and Gisvold’ s Textbook of Organic Medicinal and Pharmaceutical Chemistry Chapter 8 Page 294 Aminoglycosides They are produced by fermentation of actinomyces Chemistry: They are named amino cyclitol/aminoglycosides, the pharmacophoric group is 1,3 diaminoinositol 1 3 Some of the alcoholic functions of these are substituted through glycosidic bonds with characteristic aminosugars Streptomycin contains the aminocyclitol Streptamine (streptidine), which is substituted on its C-4 hydroxyl group by the branched sugar α-L-streptose, which itself is substituted by αL-methylglucosamine. Streptamine α-L-streptose Discovered in (1952), treated TB α-L-methylglucosamine 2-Deoxystrepamine containing aminoglycosides includes; kanamycin, neomycin, gentamycin, paromomycin and tobramycin Spectinamine containing like: Spectinomycin Characters; 1) Potent broad spectrum bactericidal. However, their oto and nephrotoxicity restricted their systemic use in serious infections. 2) Freely water soluble at all pHs, basic, poorly absorbed from GIT (less than 1%). Thus, some of them like; kanamycin, neomycin and paromomycin are used for GI infections. Also, used parentrally as IM injection. Recently, tobramycin has been spread successfully into the lung to treat Pseudomonas aeruginosa in cystic fibrosis (reduced toxicity). 3) Highly excreted in the active form in urine. Mode of action They act directly on the bacterial ribosome to inhibit the initiation of protein synthesis. Bind to the 30S ribosomal subunit to form a complex that is unable to initiate proper amino acid polymerization. The formation of this non sense protein destroys the semipermeability of the bacterial cell membrane. Depending on their concentration they act as bacteriostatic or bactericidal agents. 1. 2. 3. Unclassified antibiotics Chloramphenicol Novobiocin Linezolid Wilson and Gisvold’ s Textbook of Organic Medicinal and Pharmaceutical Chemistry Chapter 8 Page 320 Chloramphenicol It is the first broad spectrum antibiotic, isolated from Streptomyces venezuelae (soil) (1949). OH Cl H N (R) Cl (R) O + N O OH O- D-(-)-Threo-2,2-dichloro-N-[2-hydroxy-1-hydroxy methyl)-2-(4-nitrophenyl) ethyl]-acetamide Can you predict the light induced hydrolytic reaction in solutions? Products of chloramphenicol Mechanism of action of chloramphenicol: (BACTERIOSTATIC) At realistic concentration each bacterial ribosome bind 1 mol of chloramphenicol at both 50S and 30S subunits resulting in inhibition of the protein biosynthesis. Ester of Chloramphenicol as prodrugs 1. Palmitate ester, (water insoluble) used in pediatric oral suspension to mask the bitter taste. Ester of Chloramphenicol as prodrugs 2. Hemisuccinate ester, (very water soluble sodium salt) used for IM or IV or subcutaneous preparations. Thiamphenicol (4-methyl sulphonyl) It is quite potent, has not been associated with aplastic anemia which is the great drawback of using chloramphenicol due to the formation of p-nitroso analogue. OH (R) Cl H N Cl (R) O O S H3C O OH Metabolism 90% is metabolized as chloramphenicol glucoronide 2% deacetylated or dehalogenated 8% excreted unchanged Adverse reactions Aplastic anemia Toxic bone marrow depression Grey baby Syndrome Hypersensitivity reactions Chloramphenicol is the drug of choice in: (1) Typhoid fever and other serious Salmonella infections; (2) Meningitis (3) Serious infection caused by B. fragilis; (4) Rickettsial infection. Chloramphenicol should only be used for serious infections in which other medicines do not work.
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