Penicillins, cephalosporins, amido penicillins


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Penicillins, cephalosporins, amido penicillins

  1. 1. Presented by:- Naveen Kadian Department of Pharma . Chemistry KLE’S College of Pharmacy Belgaum-10
  2. 2. CONTENTS  Antibiotics and its Introduction  β- Lactam antibiotics  Penicillins Introduction Nomenclature Stereochemistry Classification Mechanism of Action Biosynthesis Structure activity relationship
  3. 3. Resistance Hypersensitivity Drug Interaction Clinical Uses  Amidopenicillins Amoxicillin Ampicillin Bacampicillin  Cephalosporins Classification Resistance Adverse Reactions Uses Biosynthesis  Recent Developments  References
  4. 4. Antibiotics  Antibiotics are the chemical substances produced by various species of micro organisms and other living systems which in small concentration kill or inhibit the growth of micro organisms. Classification β- Lactam antibiotics Monobactams Aminoglycosides Tetracyclines Macrolides Lincomycins Polypeptides
  5. 5. β- Lactam antibiotics  These includes both penicillins and cephalosporins.  The name “lactam” is given to cyclic amides and is analog to the name “lactone”, which is given to cyclic esters.  This ring ultimately proven to be the main component of pharmacophore.  This ring is more reactive and sensitive to nucleophilic attack when compared to normal planar amides.
  6. 6. Penicillins  In 1928 Alexander Fleming accidentally discover the antibacterial property of penicillin.  1940 Flore extracted the penicillin from the penicillium culture and analyzed its antibacterial activity.  They are destroyed by the enzyme amidase and β- lactamase.  The correct structure was analyzed by X-ray crystallography in 1954.
  7. 7. Nomenclature  According to chemical abstract naming starts from sculpture atom and is called 5-acyl amino -2,2- dimethyl penam 3-carboxylic acid  But in USP naming starts from nitrogen atom (4-thia- azobicyclo) heptones.
  8. 8. N S NH CO O H O COR 1 2 34 56 7 N S C O O H O P enicillanic A cid N S O Penam
  9. 9. Stereochemistry N S NH CO O H O COR 1 2 34 56 7 It contains three chiral carbon atoms at C3, C5 and C6. C6-L configuration, C3 and C6 chiral centers are trans to each other. All synthetic and semi synthetic penicillin have same absolute configuration that of natural 3S:5S: 6R
  10. 10. Classification of penicillins 1. Natural penicillins: Ex: penicillin-G 2. Semi synthetic penicillins Penicillinase resistance Pencillins Ex; Methacillin, oxacillin, cloxacillin. 3. Extended spectrum Penicillins  Amino Penicillins: Ex: Ampicillin, Bacampicillin, Amoxicillin.  Carboxy penicillins: Ex; Carbicillin, Ticarcillin.  Ureido penicillins: Ex; Pipericillin, Mezlocillin.
  11. 11. Mechanism of action Mainly interferes with cell wall synthesis of bacteria. These drugs inhibit the enzyme transpeptidase which is responsible for cross linkage of peptidoglycan during bacterial cell wall synthesis.
  12. 12. Biosynthesis of Penicillins N C H C H O C O O C4 H9 te r-b u tyl-p h th a lim id o m a lo n a ld e h yd e + S H C H C NH2 C O O H D -p e n icilla m in e C o n d e n sa tio n N C H S C O O C4 H9 N H C O O H N H2 - N H2 H cl NH2 C H S C O O H C O O C4 H9 N H p h e n o xy a ce tyl ch lo rid e trie th yl a m in e
  13. 13. S CO O H COC H2 O NHC H HCl Pyridine 1. KO H (one equiv.) 2. N,N dicyclo-hexyl carbomide N S CO O H NHCO NH CO O H O C H2 O Penecillin-V.
  14. 14. Structural activity relationship N O β- Lactam ring and R should be cyclic, aromatic or heterocyclic for their minimal activity. Substitution on α-position of benzyl penicillin have resistance to acid hydrolysis. Increase in stability is due to electron withdrawing group on amide carbonyl group. α -carbon atom of an acyl group could be a part of an aromatic or heterocyclic ring . Ex: cloxacillin, oxacillin.
  15. 15.  Substitution at ortho position of phenyl ring increases steric hindrance of acyl group thus increase β- lactamase resistance.  Nature of acyl amino side chain determines the plasma protein binding.  Substitutions of lipophillic group increases the protein binding Ex: oxacillin and cloxacilin have 80-90% protein binding, where as ampicillin and amoxicillin have 20- 30% protein binding.
  16. 16. Resistance and Hypersensitivity  Resistance may be intrinsic and involve decreased cellular uptake of drug or lower binding affinity to PBPs.  β-lactamase enzymes produced by micro organism catalyze hydrolysis of β-lactam bond and inactivates β-lactam antibiotics.  Allergy results from the formation of an allergen when the beta-lactam ring reacts with a terminal amine on a lysine residue in a polypeptide.  Every time a person is exposed to this allergen, immune system causing rash most commonly and sometimes an anaphylactic reaction.
  17. 17. Penicillin Hypersensitivity  Some specific symptoms including: an itchy rash, swelling of the throat/mouth area and difficulty breathing.  A simple skin allergy test can be performed to determine allergy to penicillin.  Erythromycin and clindamycin are alternative choices  Because the origin of allergy is a reaction with host protein , the side effect is caused by pharmacophore and is unlikely to over come by molecular manipulation.
  18. 18. Drug interactions  Oral contraceptives – Penicillins may interact with oral contraceptives and decrease the effectiveness of the oral contraceptives.  Probenecid – This may compete with penicillin for renal tubular secretion and result in higher serum levels of penicillin.  Methotrexate - decrease the ability of kidneys to remove methotrexate from your body resulting in increased levels of methotrexate in the body.
  19. 19. Clinical uses  Urinary tract infections  Respiratory tract infections  Meningitis  To treat Gonorrhea, Syphilis, typhoid, bacillary dysentery.  Sub acute bacterial endocarditis.  Bone and joint infections.  Bronchitis, Pneumonia.  Skin and Soft tissue infections.
  20. 20. Amido penicillins  6β-acylamino side chain replacement usually results in loss of activity.  In 1972 Lund and tiring reported that 6-amidino penicillinic acids have good activity against G-ve bacteria.  SAR studies reviewed that N,N-dialkyl formamides tend toresemble the analogs of pencillins active against G-ve bacteria.  Ex: homopiperidine derived from formamide, Mecillinam. N C H N N S C O O H O
  21. 21.  Mecillinam's mechanism of action differs from other - lactam antibiotics, that its primary target is penicillin- binding protein 2.  mecillinam and ß-lactam antibiotics showed synergy in most instances.  Synergy was not found with combinations of mecillinam and aminoglycosides, chloramphenicol, tetracycline, or polymyxins.  Mecillinam was combined with amoxicillin, carbenicillin, and cefoxitin and tested against most members of the Enterobacteriaceae and Pseudomonas.
  22. 22. Synthesis of Mecillinam NC H O Me O Me + S N O C O O H NH2 6-am ino penicillanic acid 1-hexam ethylenim ine dim ethyl acetal E ther S N O C O O H N C H N M ecillinam
  23. 23. Amoxicillin  It is derived semi-synthetically from the fermentation of Penicillium sp.  The C-6 substitute contains a secondary amine that can be protonated as well as a phenol group that can be deprotonated.  The carboxylic acid at position 3 is also capable of deprotonation.  When these groups are ionized, the molecule contains a net negative charge and therefore is less Zwitterionic and more capable of being orally absorbed
  24. 24. Mechanism of action  Inhibition of the bacterial cell wall biosynthesis, preventing cross-linking of peptidoglycan.  It is an alternative substrate for transpeptidases because of its structural similarity to the transition state of the Ala- Ala terminal during cross-linking. Dosage forms and dosing. Amoxicillin is available as 250 mg and 500 mg capsules.  500 mg and 875 mg tablets.  125mg, 200 mg, 250 mg, 400 mg chewable tablets.  50mg/5ml, 125mg/5ml, 200mg/5ml, 250mg/5ml, and 400mg/5ml suspensions.
  25. 25. Ampicillin  α- amino moiety induces its ability to cross cell wall, hence play an important role in activity.  Water soluble, stable in acidic condition.  Absorbed from intestinal tract, excreted rapidly unchanged in kidney.  D (-) Ampicillin is active.  Interactions: hydrocortisones inactivates when mixed in I V solutions.  Dose; 0.5-2gms.  AMPILLIN, ROSCILLIN, BIOCILLIN. AMOXL
  26. 26. Synthesis N S COO H NH O CO N S COO H NH2 O COO HC H NH2 5-amino penicillanic acid + (1) Acylation (2) NaOH C H NH2 Ampicillin amino-phenyl acetic acid
  27. 27. Bacampicillin  Ester of ampicillin (ethoxy carbonyl oxyethyl ester)  Prodrug of ampicillin after oral absorption hydrolysed by esterase in plasma to form ampicillin.  Having high tissue penetration.  Dose: 400-800mg twice a day (PENGLOBE) N S NH O COC H NH2 CO O C H CO O C2 H5 C H3
  28. 28. Prodrugs of Ampicillin  Pivampicillin  Bacampicillin  Talampicillin
  29. 29. Cephalosporins  Cephaolosporins are the second major class of β- lactam antibiotics.  They differ from penicillins as they have 6 membered dihydrothiazine ring.  The first member of this series was extracted from Cephalosporium acremonium in 1956.
  30. 30. Classification of Cephalosporins  First Generation Drugs Parentral Cephalothin Cefazolin Oral Caphalenin Caphradine Cefadroxil
  31. 31.  Second Generation Parentral Cefuroxime Cefoxitin Oral Cefaclor Cefuroxime axetil  Third generation Parentral Cefotaxime Ceftizoxime Ceftrixone Ceftazidine Cefoperazone
  32. 32.  oral  Cefixime  Cefpodoxime proxetil  Cefdinir  Ceftibutem Fourth Generation Parentral Cefepime Cefpirone
  33. 33. Resistance  alteration in target proteins (PBP) reducing the affinity for antibiotic  impermiability elaboration of β- lactamase Inhibition of β- Lactamase  polar group in aminoacyl moeity (cefomandole)  steric factor (cefoperazone)  methoxyl group at 7th position (cefuroxime, cefotaxime)
  34. 34. Adverse Reactions  pain after i.m. administration (cephalothin)  diarrohea (cephradine, cefoperazone)  hypersensitivity  nephrotoxicity (cephaloridine, cephalothin)  bleeding (cefaperazone, ceftriaxone)  neutropenia, thrombocytopenia
  35. 35. Uses-  allergic reactions  respiratory, urinary, soft tissues infections  staphylococcal infection  septicaemia  surgical prophylaxis  meningitis  gonorrhoea  typhoid
  36. 36. Biosynthesis- C O NH HO O C NH2 O N S C H3 C H3 C O O H C O NH HO O C O N S C H3 C H3 C O O H H H NH2 C O NH HO O C O N S H H C H3 C O O H NH2 1 3 Is openic illin N 2 H H epimerizati on Oxidation hydroxylation
  38. 38. Recent articles- Extraction of penicillin G from aqueous solutions: Analysis of reaction equilibrium and mass transfer Authors- Department of Chemical & Petroleum Engineering, United Arab Emirates University, P.O. Box 17555, Al Ain, United Arab Emirates Abstract- Analysis of the reaction equilibrium and mass transfer in the extraction of penicillin G (Pen G) into an organic phase is an important research area to develop a cost-effective process for its separation from an aqueous fermentation media. In order to evaluate this, equilibrium experiments were first carried out to select the organic phase (composed of the carrier and solvent) that gives good values for the distribution of penicillin G between the aqueous and organic phases. An organic phase of Amberlite LA-2 in any of the solvents (Shellsol TK/butyl acetate/tributyl phosphate) gave high distribution coefficient and the stoichiometry of the reaction has been shown to follow a simple ratio of 2:2. The performance of the organic phases was evaluated in a membrane contactor and very high percentage extraction was achieved. The extraction was performed by contacting a “feed” solution containing penicillin G (flowing in the fiber side) with an “organic phase” of Amberlite LA-2 in one of the solvents (flowing on the shell side) of the contactor. The antibiotic solutes formed complex with the Amberlite LA-2 molecules which were transported across the fiber wall to the shell side and extracted in the organic phase. The extraction in once-through mode was low and the feed/organic solutions need to be recycled to increase the percentage extraction. In the recycle mode operated at flow rates of 3.6– 4.4 mL/s, an extraction of 90–98% was achieved. A simple mathematical model and its semi-analytical solution presented here can be used to determine the overall mass transfer coefficient using the experimental values of the distribution coefficient, operating parameters and the dimensions of the membrane module
  39. 39. Hybrid penicillin acylases with improved properties for synthesis of β-lactam antibiotics Authors- Simon A.W. Jager , Peter A. Jekel and Dick B. Janssen Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747 AG Groningen, The Netherlands Abstract- Penicillin acylase (PA) from Escherichia coli can catalyze the acylation of 6- aminopenicillanic acid (6-APA), a conversion that is applicable in the biocatalytic preparation of semi-synthetic β-lactam antibiotics such as ampicillin. The efficiency of this kinetically controlled conversion, in which an amide or ester acts as the acyl donor, is dependent on the kinetic properties of the enzyme. To further improve the synthetic properties of PAs, family gene shuffling was performed with the PA-encoding genes of the PAs from E. coli, Kluyvera cryocrescens and Providencia rettgeri. Of these three PAs, the E. coli enzyme possessed the best properties for the synthesis of ampicillin. Shuffled recombinant libraries were pre- screened for activity by growth selection, followed by testing the catalytic performance in ampicillin synthesis using HPLC. Three clones with improved synthetic properties were selected and sequence analysis showed that the shuffled genes were hybrids of the PA- encoding genes from E. coli and K. cryocrescens, with additional point mutations. The hybrid enzymes displayed a 40–90% increase in the relative rate of acyl transfer to the β-lactam nucleus during ampicillin synthesis. This increase was not accompanied by a reduction of synthetic activity that has previously been reported for mutants of E. coli PA constructed by site-directed mutagenesis. Similar improvements in acyl transfer were obtained for the synthesis of amoxicillin, cephalexin and cefadroxil, making the new hybrid enzymes interesting candidates for the biocatalytic synthesis of several β-lactam antibiotics.
  40. 40. References 1. Block J.K, beale J. M. Wilson and Gisvold’s text book of organic medicinal and pharmaceutical chemistry.11th Edition london: lippincot williams and wilkins.; 2004; 299-318. 2. William D. A, Thomas.L. Foye’s Principals of medicinal chemistry, 6th Edition Lippincott Williams and Wilkins. Philadelphia; 2007; 1046-55. 3. Tripathi KD. Essentials of Medical Pharmacology. 5th Edition New Delhi: Jaypee Brothers Medical Publishing (P) Ltd.; 2004; 770-4. 4. Abraham D. J, Burgers medicinal chemistry and drug discovery,6th Edition ; vol 2; new jersey: John willey and sons, 2003; 626-637. 5. Corwin Hansch. Comprehensive Medicinal chemistry.vol 2: Pergamon Press, Newyork; 627-630. 6.