Chemistry and SAR of Protein Synthesis Inhibitors

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This presentation is about the chemical aspects and SAR of Tetracyclins, Macrolides and Chloramphenicol. This is designed with preference for students of medicinal chemistry. The PPT contains contains the description of the synthesis, mechanism of action and SAR of the protein synthesis inhibitors.

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PROTEIN SYNTHESIS INHIBITORS Chapter:11 Unit:3 Chemotherapeutic Agents By- Gaurav Kayal ( M.Pharm ) Assistant Professor (Pharmaceutical Chemistry)

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Contents Tetracyclines Introduction Structure Classification SAR Mechanism of action Stability under acid condition Formation of 4-epitetracycline Stability under base condition Formation of metal chelates Uses

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Chloramphenicol Introduction Stereochemistry Chemical property SAR Mechanism of action Synthesis Chloramphenicol palmitate Chloramphenicol sodium succinate Uses

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Macrolides Introduction SAR Mechanism of action Erythromycin Unstability under acid condition Modification of Erythromycin Strategy for eryhtromycin modification Telithromycin Uses

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TETRACYCLINES

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Introduction 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. By Gaurav Kayal

Structure:

Structure 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. By Gaurav Kayal

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6-Methyl-4-(dimethylamino)-3,6,10,12,12a-pentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide By Gaurav Kayal

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Classification: By Gaurav Kayal Substitution R1 R2 R3 R4 Tetracycline H CH3 OH H Chlortetracycline Cl CH3 OH H Oxytetracycline Cl CH3 OH OH Demeclocycline Cl H OH H Methacycline H CH2 - H Doxycycline H H CH3 OH Minocycline N(CH3)2 H H H

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Structure Activity Relationship (SAR): By Gaurav Kayal 4 cyclic rings are important for activity and derivative containing less than 4 rings is inactive. 6-demethyl, 6-deoxy tetracycline posses broad spectrum anti-bacterial activity. The integrity of substituent at carbon 1, 2, 3, 4, 10, 11, 11a and 12 represent the hydrophillicity. Slight modification is tolerated in ring A. Enolised tricarbonylated methane system at C1 to C3 must for good activity. Replacement of amide at C3 position with other functional group like aldehyde, cyano reduces activity. Mono alkylation of amide reduces activity which is directly proportional to size of alkyl group. Amino alkylation by Mannich Reaction are more water soluble than tetracycline. Dimethyl amino group at 4 th position must have alpha orientation.

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By Gaurav Kayal 4- epitetracycline is less active due to beta orientation. Removal of 4-dimethyl amino group further decrases activity. Activity is largely retained in primary and secondary amines but decreases with higher aklyl amines. Ring fusion between A and B ahould be cis fused with beta-OH group at C12 is essential for activity. Esters at C12a is inactive except formyl esters. Alkylation of C11a also leads t inactive compounds. Inonisable beta ketones is essential at C11 and C12. Substitutions at C 5, 6, 7, 8, and 9 represent largely hydrophobic northern and western faces of molecule. 5 alpha group in oxytetracycline and doxycycline influences pharmacokinetic properties but does not alter the activity. Electron withdrawing group at C7 like Cl, nitro or electron donatin dimethyl amino; both enhances the activity.

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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. By Gaurav Kayal

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By Gaurav Kayal

Stability under acid condition:

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 . By Gaurav Kayal

Formation of 4-Epitetracycline:

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-4 β -epimer occurs. Under acidic conditions, a 1:2 equilibrium is established in solution within a day. By Gaurav Kayal

Stability under base condition:

Stability under base condition In basic medium, ring C of tetracycline is opened to form isotetracycline. By Gaurav Kayal

Formation of metal chelates:

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. By Gaurav Kayal

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Uses: By Gaurav Kayal Tetracyclines are generally used in the treatment of infections of the urinary tract and the intestines and are also used in the treatment of chlamydia, especially in patients allergic to  β- lactams and macrolides. Their most common current use is in the treatment of moderately severe acne and rosacea (tetracycline, oxytetracycline, doxycycline). Doxycycline is also used as a prophylactic treatment for infection by  Bacillus anthracis  (anthrax) and is effective against  Yersinia pestis , the infectious agent of bubonic plague. It is also used for malaria treatment and prophylaxis, as well as treating elephantiasis. Tetracyclines remain the treatment of choice for infections caused by chlamydia, Rickettsia, brucellosis and spirochetal infections.

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CHLORAMPHENICOL

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Chloramphenicol is an antibiotic produced by Streptomyces venezuelae and other soil bacteria that was first discovered in 1947 and is now exclusively produced synthetically. By Gaurav Kayal Introduction D-(-)-threo-1- p -nitrophenyl-2-dichloroacetamido-1,3-propanediol

Stereochemistry:

By Gaurav Kayal With two chiral centers it is one of four diastereomers only one of which (1R, 2R) is active. Stereochemistry

A molecule, with two chiral centers, has four isomers (diastereomers). :

A molecule, with two chiral centers, has four isomers ( diastereomers) . By Gaurav Kayal

Chemical properties:

Chemical properties By Gaurav Kayal

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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. By Gaurav Kayal

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Structure Activity Relationship (SAR): By Gaurav Kayal Para nitro phenyl can be replaced by other aryl structures without appreciable loss of activity. Substitution of phenyl ring other than nitro group or any other functinal group does not decreases the activity. But all such compounds have less activity than chloramphenicol. Compound with 2- NHCOCF3 substitution is 1.7 times more active than chlramphenicol. Stereochemistry of side chain is important for activity. Conversion of C1 alcohol group to keto group causes appreciable loss of activity.

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By Gaurav Kayal Mechanism of action:

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Synthesis By Gaurav Kayal

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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 By Gaurav Kayal

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  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%. By Gaurav Kayal

Uses::

Uses: 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 β -lactam allergic patients, anaerobic infection , rickettsial infections, and so on . By Gaurav Kayal

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MACROLIDES

Introduction:

Introduction 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. By Gaurav Kayal

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Structure Activity Relationship (SAR): By Gaurav Kayal A lactone ring, a ketone grup and a amino sugar are the basic characteristic groups that are present in a macrolide and are desired for activity. The amino sugar present must be glycosidically bonded. Lactone ring contains 12, 14, 16 atoms in cyclic ring along with olephinic group and hence called macrolide. neutral sugars are also present in addition to glycosidically bonded sugars. Dimethyl amino group provides basic properties to macrolides.

Mechanism of action:

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. By Gaurav Kayal

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By Gaurav Kayal

Erythromycin:

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. By Gaurav Kayal

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A and B A C-12=-OH B C-12=-H A and C A C-3"=OCH 3 C C-3"=-OH By Gaurav Kayal

Unstablity under acid condition:

Unstablity under acid condition By Gaurav Kayal

Simply modification of erythromycin -Ester Pro-drug:

Simply modification of erythromycin -Ester Pro-drug By Gaurav Kayal

Strategy for erythromycin modification:

Strategy for erythromycin modification By Gaurav Kayal

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By Gaurav Kayal

Erythromycin derivatives:

Erythromycin derivatives By Gaurav Kayal

Telithromycin:

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. By Gaurav Kayal

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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-OCH 3 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 strains By Gaurav Kayal

Uses::

Uses: Antibiotic macrolides are used to treat infections caused by Gram-positive bacteria (e.g.  Streptococcus pneumoniae ) and  Haemophilus influenzae  infections such as respiratory tract and soft-tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin, and, therefore, macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic streptococci, pneumococci , staphylococci, and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against Legionella pneumophila, mycoplasma, mycobacteria, some rickettsia, and chlamydia. By Gaurav Kayal

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THANK YOU For Doubts/ Queries- Mr. Gaurav Kayal Assistant Professor (Pharmaceutical Chemistry) ( Ph-9009991186, [email protected])

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