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Transcript
Lecture 5 Medicinal Chemistry 1 PC 509 Prof. Dr/ Ghaneya Sayed Hassan [email protected] 1 Macrolides Properties: • Isolated form Sterptomyces species. • Lead compound is Erythromycin. Spectrum: • Nearly as penicillin G narrow spectrum [used as alternative for patients allergic to penicillins]. • Drug of choice for chlamydial infections, mycoplasma, pneumonia, Corynebacterium diphtheriae & Ligionella pneumophila. M.O.A: Specific inhibitor of bacterial protein biosynthesis by binding to the 50S ribosomal subunit interfere with translocation reactions & formation of initiation complexes inhibit protein synthesis bacteriostatic [may be cidal at doses] Safe to human [not affect 60 S unit] selective chemotherapy. 2 Resistance: due to: 1) Inability of m.o. to take up the drug. 2) Produce enzymes that methylate specific adenine residue to erythromycin binding site affinity of erythromycin to bind. 3) Presence of plasmid-associated erythromycin esterase. Side effects: (1) GIT problems. (2) Cholestatic jaundice: especially with Erythromycin Estolate [result from hypersensitivity reaction bile becomes granular in bile duct its flow back up into circulation]. (3) Ototoxicity: transient deafness [especially at doses]. (4) Erythromycin level of simultaneously administered anticoagulants, anti-diabetetics, cyclosporine, carbamazepine…. By inhibition of microsomal enzymes. “Metabolizing microsomal enzymes’ inhibitors” (5) Not used for patients with hepatic dysfunction drug accumulation in liver. 3 Chemical properties: (1) Large lactone ring [cyclic ester] with 12-17 atoms so, the name Macrolides. (2) With 2 or more sugars attached to this ring one of them is amino sugar [so, marcrolides are weakly basic]. (3) Free bases are water insoluble. Stability: In neutral medium macrolides are stable. In acidic medium hydrolysis of glycosidic bonds. In basic medium saponification of lactone ring [opening]. 4 Erythromycin Obtained by fermentation of Sterptomyces erythereus. Desosamine CH3 O CH3 HO 11 12 CH3 C2H5 8 9 10 HO 7 CH3 6 HO R1 O Erythronolide 2 O CH3 6' CH3 1' O 5' 2' CH3 3' CH3 OH Oxo Ethyl 6'' O 5'' CH3 CH3 3 14 O 1 O 1'' 5 4 13 2'' 2,4,6,8,10,12 3,5,6,11,12 1,9 13 N - Me2 3'' 4'' 4' R1 R2 Erythromycin A OH CH3 Erythromycin B H CH3 Erythromycin C OH H OH OR2 Used usually as mixture of 90% Erythromycin A + 10% Erythromycin B + traces of Erythromycin C. Cladinose Consist of : ► Erythronolide [aglycone part, large lactone ring, 14-membered ]. ► Desosamine [amino sugar] ►5 Cladinose [neutral sugar]. To overcome its bitter taste & its irregular absorption: Result from acid destruction & adsorption of food. (1) Enteric coated & delayed-release dose dosage forms: Over come bitter taste but not solve problem of poor absorption. (2) Erythromycin Salts: Salts formed on dimethyl amino group of Desosamine. ☻HCl salt moderate solubility. ☻ Glucepate & Lactopionate freely soluble in water I.V. ☻ Stearate with solubility tasteless [combined with enteric coating] hydrolyzed in intestine to free erythromycin absorption. (3) Erythromycin Esters: Estolate: [C2’’-propionyl ester] & [N-lauryl sulfate salt] with superior oral absorption [ acid stable + intrinsic absorption + oral absorption not affected by food]. Ethyl succinate: mixed double ester [ one carboxylic of succinic acid react with C2’’ of erythromycin & other carboxylic react with ethanol]. It’s insoluble in water [used as oral suspension for pediatrics as it masks bad taste of erythromycin] 6 SALT ESTER Desosamine CH3 O CH3 HO RO 9 10 CH3 HO 6 O CH3 O OH CH3 C2H5 R Salt 1. Erythromycin Base H ----- 2. Erythromicine HCl H HCl COCH2CH3 CH3(CH2)11OSO3H N - Me2 3. Erythromicine Estolate 4. Erythromycin Ethylsuccinate CH3 O 14 O O CH3 CH3 O Erythronolide CH3 OH OCH3 CO(CH2)COOC2H5 ----- 5. Erythromycin Gluceptate H Glucoheptanoic acid 6. Erythromycin Lactobionate H Lactobiono-S-lactone 7. Erythromycin Stearate H CH3(CH2)16COOH Cladinose N.B: Erythromycin esters not considered as latent prodrugs, as they are active itself & their activity not depend on their hydrolysis. But they are partially hydrolyzed to free drugs in blood. 7 Erythromycin is Unstable to Acids due to Rapid Cyclic Ketal formation inactivation + GIT cramps. H+ H+ N - (CH3)2 O HO OH 12 HO O O HO O O - H2 O OH O O O O O O OH OCH3 Active Macrolide RO RO HO O 6 N - (CH3)2 N - (CH3)2 RO 9 O Hemiketal O HO O O O OH OCH3 O O O O O Cyclic Ketal OH OCH3 Inactive + causing GIT cramps So, we make semi-synthetic analogues to prevent this ketal formation. 8 Semi-synthetic analogues Clarithromycin [Klacid®] CH3 N - Me2 HO O CH3 CH3 HO CH3O 6 O CH3 O OH CH3 C2H5 CH3 O O O CH3 CH3 O CH3 OH OCH3 Semi-synthetic drug from erythromycin by methylation of 6-OH etherification. 6-OH involved in ketal formation which form inactive drug + GIT cramps. Methylation of 6-OH ADVANTAGES: (1) No cyclic ketal formation [inactivation + GIT cramps]. (2) absorption & better blood level. (3)9 lipophilicity & less frequent dose for mild infections. (4) gastric upset. Azithromycin [Zithromax®, Azithrocin®] CH3 9 CH3 8 N - Me2 HO N 9a CH3 HO 10 CH3 HO O CH3 O OH CH3 C2H5 CH3 O O O CH3 CH3 O CH3 OH OCH3 Semi-synthetic ring-expanded analogue [15-membered] by insertion of N-methyl between C9-C10 + removal of C=O. Not form internal cyclic ketal. ADVANTAGES : (1) No cyclic ketal formation [inactivation + GIT cramps] (2) More acid stable. (3) With longer duration [once daily] 10 Greater G-ve activity > Erytho- & Clarithromycin. (4) Chloramphenicol O H O2N 1 NH 2 Cl C CH Cl 3 CH2 OH OH H D(-) threo-2,2-dicloro acetamido-1-(4-nitro phenyl) propane-1,3-diol ►Natural antibiotic; produced by fermentation of Streptomcyes venezuelae. But now produced by total synthesis [less expensive]. ►Used orally or I.V. 11 Spectrum: 1) Broad spectrum, active ≠ rickettsial infections. 2) Drug of choice in Salmonella infections [typhoid fever]. 3) against H.influenza, -lactamase producing strains & meningococcal infections. 4) With excellent activity ≠ anaerobes. 5) Now mostly used as eye drops for ophthalmic infections. M.O.A: Binds to 50 S ribosomal subunits interfere with action of peptidyl transferase block attachment of amino acids to nascent peptide chain on ribosomes inhibit protein synthesis Bacteriostatic. 12 Side effects: (1) Bone marrow depression: May cause fatal blood dyscrasias [aplastic anemia, hypoplastic anemia, thrombocytopenia & granulocytopenia]. (2) Gray syndrome: form of CVS collapse; Occur when given for premature & newborn infants [with undeveloped glucuronidation & undeveloped renal function] accumulation of chloramphenicol poor feeding, breathing, CVS collapse [gray baby] & death. So, not recommended in 1st two weeks of life. (3) Inhibition of hepatic mixed function oxidases: block metabolism of drugs e.g. warfarin, tolbutamide , phenytoin their concentration. 13 Metabolism: • Mainly excreted in urine. • Major metabolite is C7-glucuronide, Minor obtained by deamination, dehalogenation & reduction of aromatic nitro group [all metabolites are inactive]. Resistance: Occur due to: (1) dose. (2) Irregular use. (3) Inappropriate use. (4) Production of enzymes chloramphenicol acetyl transferase acetylation of 1-OH & 3-OH 1-acetoxy & 1,3-diacetoxy derivatives inactive. (5) Inability of the drug to penetrate m.o. 14 SAR: Replacement of phenyl group with: - aromatic or alicyclic moities --> inactive Cpds - Nitrothienyl derivative has activity << chloramphenicol. (*) two chiral centres is essential for activity & only D- (-) (1R,2R) threo has marked activity. H O 2N * C OH - NO2 if replaced with strong electronwithdrawing gps ----> active cpds e.g. Acetyl gp ( cetophenicol ) & Methyl sulphonyl ( thiamphenicol) - if replaced by CN , CONH2 , halogen , OH & SO2R----> inactive cpds - NO2 shifting from P-position ----> reduce activiry. 15 * NH R C CH2 OH H The amine propanediol side chain is the most specific part: - 1ry alcohol & 2ry alcohol ----> essential for activity - Me subistitution for H on C2 -----> No activity. - If R= CH2N3 (azidamphenicol ) OR R= COCHBr2 -----> Both give active Cpds. N.B. The following are active compounds: Cetophenicaol Thiamphenicol O O O H3C C NH 1 OH 2 C CH2 3 O CH(Cl)2 H3C OH S 1 OH O NH 2 Azidamphenicol O2N 1 OH NH 2 CH2 CH2 3 N3 O2N OH 1 OH O2N 1 16 CH2 3 CH(Cl)2 OH O O S C OH NH 2 C CH2 3 CH(Cl)2 OH Less active than chloramphenicol NH 2 C CH2 3 CH(Br)2 OH Prodrugs of chloramphenicol: [C3-esters] Chloramphenicol Chloramphenicol Palmitate Hemisuccinate O H NH O2N 1 2 O Cl H NH C CH Cl 3 CH2 O CO (CH2)14 CH3 OH H Insoluble in water. To overcome bitter taste. Used for pediatric oral suspensions. O2N 1 2 Cl C CH Cl 3 CH2 O CO CH2 CH2 COOH OH H Water soluble used for injection to overcome poor water solubility. Esters are inactive hydrolyzed in vivo releasing active form. 17 Stability: • Very stable in solid form. • In solution hydrolytic & light-induced reactions; depending on pH, heat & light: [1] Acid-catalyzed hydrolysis of amide: O H 1 O2N NH 2 Cl C CH H Cl 3 CH2 OH O2N OH H 1 NH2 2 3 CH2 OH + O HO Cl C CH Cl OH H 1-(p-nitrophenyl)-2-amino propan-1,3-diol dichloro acetic acid [2] Alkaline hydrolysis of -chloro ,-dihydroxy derivative. O H O2N 1 NH 2 OH H 18 Cl O C CH Cl 3 CH2 OH H O2N 1 NH 2 OH H OH C CH OH 3 CH2 OH Synthesis of Chloramphenicol: O O2N C CH3 Br2 Ac-OH 1. Hexamine (CH2)6N4 O O2N C CH2 Br O O2N 2. HCl P-nitro acetophenone O OH NH C CH3 Al isopropoxide O2N C CH O2N H CH2 OH no reduction for NO2 Erythro + Threo O O2N DL-threo 19 Resolution D-(+) camphor sulfonate CH2O NH C CH3 C CH CH2 OH fractional crystallization H+ NH2 C CH H CH2 OH C CH2 NH2 Acetic anhydride O OH .HCL NaHCO3 O OH O2N NH2 C CH H CH2 OH D(-)-threo Cl C O O2N C CH2 NH C CH3 Cl CH Cl dichloroacetyl Cl O Cholramphenicol Mechanism of action: 1- -lactam antibiotics: Inhibitors of cell wall synthesis. 2- Tetracyclines: Bind to 30 ribosomal subunit of bacteria interfere with protein biosynthesis leading to bacteriostatic. 3- Aminoglycosides: Bind to 30 S ribosomal subunit of m.o. through specific receptor protein inhibit initiation of protein synthesis. 4- Macrolides: Bind to 50 S ribosomal subunit inhibit protein synthesis. 5- Chloramphenicol: Bind to 50 S ribosomal subunits inhibit protein synthesis. 20 Cyclic peptides antibiotics The usual physiologically significant peptides are linear. Several bacterial species, however, produces antibiotic mixtures of cyclic peptides some with uncommon amino acids and some with common amino acids but with the D absolute stereochemistry. These cyclic substances often have a pendant fatty acid chain. Mode of action: (Disruption of bacterial membrane function) These drugs are usually water soluble and are highly lethal to susceptible bacteria as they attach themselves to the bacterial membrane and interfere with their semi permeability so that essential metabolites leak out and undesirable substances pass in. 21 Side effects: They are highly toxic in humans so their use is reserved for serious situations where there are few alternatives or to topical uses. Resistance: Bacteria are rarely able to develop significant resistance to this group of antibiotics. Stability: They are generally unstable to solutions should be protected from heat, light and extremes of pH. Cyclic peptides antibiotics: They are: 1-Vancomycin 2- Teicoplanin 3-Quinupristin 4-Dalfopristin (=Streptogramins). 5-Capromycin 6-Bacitracin 7-Polmyxin B 8-Colistin 22 Bacitracin It is a mixture of similar peptides produced by fermentation of Bacillus subtilis. Uses: It is active mainly against gram (+) microorganisms and is used topically or intramuscularly against staphylococci resistant to other agents. It is also used orally for enter pathogenic diarrhea and, especially, against Clostridium difficile. It can also be used for preoperative bowel sanitization. It is neuro and nephrotoxic restricted in uses. Zn2+ enhances its activity. Mode of action: 1- Inhibition of peptidoglycan biosynthesis. 2- Disruption of plasma membrane function. 23 Polymyxin B It is produced by fermentation of Bacillus polymyxa. Uses: It is active against gram (-) microorganisms. It is used I.M or I.V to treat serious urinary tract infections, meningitis and septicemia caused by Pseudomonas aeruginosa. It is also used orally to treat enter pathogenic E. coli and Shigella sp. diarrheas. It is neuro and nephrotoxic especially when given parentrally (restricted in uses). Mode of action: It binds to phosphate groups in bacterial cytoplasmic membranes and disrupts their integrity. 24 Colistin Colistin sulphate is a cyclic polypeptide drug produced by Bacillus polymyxa var. colistinus. Uses: It is bactericidal mainly to gram (-) bacteria. It is neuro and nephrotoxic especially when given parentrally (restricted in uses). It is used orally against diarrhea due to E. coli and shigella species. Mode of action: Colistin causes destruction of the integrity of cytoplasmic membrane. Colistin is polycationic and has both hydrophilic and lipophilic moieties. These interact with the bacterial cytoplasmic membrane, changing its permeability. This effect is bactericidal 25