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Chapter 8 Antibiotics Section 1. β–Lactam Antibiotics(2)

Chapter 8 Antibiotics Section 1. β–Lactam Antibiotics(2). Wei-Min Chen, Prof. Department of Medicinal Chemistry, JNU. Topics in This Class. Cephalosporins Non-typical β-lactam antibiotics and inhibitors of β-lactamase Tetracyclines

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Chapter 8 Antibiotics Section 1. β–Lactam Antibiotics(2)

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  1. Chapter 8 AntibioticsSection 1. β–Lactam Antibiotics(2) Wei-Min Chen, Prof. Department of Medicinal Chemistry, JNU

  2. Topics in This Class • Cephalosporins • Non-typical β-lactam antibiotics and inhibitors of β-lactamase • Tetracyclines Key drugs: Cephalosporins ,Cephalexin, Cefotaxime Sodium Tough issues: inhibitors of β-lactamase

  3. Cephalosporins

  4. The cephalosporins are a subgroup of β–lactam antibiotics, whose bicyclic system, called the cepham nucleus, consists of a four-member β–lactam ring fused through the nitrogen and adjacent tetrahedral carbon atom to a second heterocycle forming a six-member dihydrothiazine ring. • C2-C3 double bond can formed conjugated structure with N1 in cephalosporins. Cephalosporins are more stable than penicillins.

  5. Cephalosporin C 7-ACA • In 1945, cephalosporin C was isolated from extracts of Cephalosporium acremonium, a fungus. • The clinical use of cephalosporin C was limited by its generally weak antibacterial activity. • As soon as 7-amino-cephalosporanic acid (7-ACA) became available, numerous novel cephalosporins were prepared by a re-acylation .

  6. 4 7 H H S C H2 R1 C N C C C O N C 2 CH2 C O R2 7-ACA Chemistry • Cephalosporin antibiotics are prepared by the addition of different side chains to 7-aminocephalosporanic acid (7-ACA). So they are semi-synthetic antibiotics. It appears that modifications at position 7 of -lactam ring are associated with alteration in antibacterial activity and that substitutions at position 3 of the dihydrothiazine ring are associated with changes in the pharmacokinetic properties of the drugs.

  7. The difference of structures between the Cephalosporins and Penicillins • Cephalosporins differ from penicillins by having the β -lactam ring fused a 6 member ring. The other difference, which is more significant from a medicinal chemistry stand point, is the existence of a functional group (R) at 3-position of the fused ring system. This now allows for molecular variations to effect changes in properties by diversifying the groups at 3-position.

  8. General Features of Cephalosporins • Compared to penicillins, • cephalosporins are relatively stable in dilute acid, • highly resistant to -lactamase, with broad antibacterial spectrum, • with higher antimicrobial activity, • and less hypersensitivity reactions.

  9. Usage Like penicillin, cephalosporins are valuable because of their low toxicity and their broad spectrum of action against various diseases. In this way, cephalosporin is very similar to penicillin. Cephalosporins are one of the most widely used antibiotics, and economically speaking, has about 29% of the antibiotic market. The cephalosporins are possibly the single most important group of antibiotics today and are equal in importance to penicillin. The structure and mode of action of the cephalosporins are similar to that of penicillin. They affect bacterial growth by inhibiting cell wall synthesis, in Gram-positive and negative bacteria.

  10. C-3 acetoxyl group makes Cephalosporin unstable in vivo Decomposition of Cephalosporins in vitro (Inactive) Decomposed by enzyme in vivo (Inactive)

  11. Structural Modification of Cephalosporin I: Relating with the antibacterial spectrum. II: Substituted with OCH3 will be stability for β-Lactamase III: S atom can be replaced by –O- or –CH2-. IV: Relating with the antibacterial activity and bioavailability.

  12. Classification of Cephalosporins • Some 50 different cephalosporins are in clinical use or at an advanced stage of development and many attempts have been made to classify these based on stability to β-lactamases, potency, antibacterial spectrum, and pharmacological properties. • Cephalosporins are divided into first-, second-, third-, and fourth-generation agents, based roughly on their time of discovery and their antimicrobial properities.

  13. Structures of first-generation cephalosporins.

  14. First-generation cephalosporins • First-generation derivatives such as cephalothin , cefazolin , and the orally absorbed cephalexin possess activity against Gram-positive bacteria, but a relatively narrow spectrum against Gram-negative strains attributed in part to their susceptibility to β-lactamases.

  15. The second-generation cephalosporins

  16. The second-generation cephalosporins The second-generation cephalosporins are • more effective against gram-negative bacteria • and more stable to -lactamase produced by gram-negative bacteria than the first-generation cephalosporins.

  17. The third-generation cephalosporins

  18. The third-generation cephalosporins • More potent against gram-negative bacteria than the first and second-generation cephalosporins. • Extended antibacterial spectrum, including Pseud. aeruginosa and anaerobes. • Less active against gram-positive bacteria than the first and second-generations.

  19. The fourth-generation cephalosporins • The fourth-generation cephalosporins show some slight further advantages. • They have similar antibacterial activity with the third generation , but more stable to -lactamase. • There is a quaternary ammonium group at position 3

  20. Synthetic Methods of Semi-Cephalosprins *The preparation of 7-aminocephalospranic Acid (7-ACA) Method 1

  21. Chemical Transformation of a Penicillin Nucleus to a Cephalosporin Nucleus. The preparation of 7-amino-3-deacetoxycephalosporanic acid (7-ADCA)

  22. 1.Cephalexin (头孢立新,头孢氨苄,先锋IV号)   • (6R,7R)-3-Methyl-7-[(R)-2-amino-2-phenylacetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate.

  23. Discovery • Learn from the experience of Penicillins modifications; • Using the side chain of Ampicillin, Amoxicillin to react with 7-ACA; • Semi-Cephalosporins cephaloglycin(头孢甘氨) was firstly obtained.

  24. Synthesis of Cephalexin

  25. 2.Cefotaxime Sodium(头孢噻肟钠) (6R,7R)-3-[(Acetyoxy)methyl]-7-[(amino-4-thiazolyl)-(methoxyimino) acetylamino]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium

  26. Cefotaxime • Cefotaxime was the first third-generation cephalosporin to be introduced. • It possesses excellent broad-spectrum activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. • Many β–lactamase-producing bacterial strains are sensitive to cefotaxime.

  27. Structural configuration was changed under light • The syn isomer of cefotaxime is significantly more active than the anti isomer against –lactamase-producing bacteria.This potency difference is, in part, duo to greater resistance of the syn isomer to the action of –lactamases. The higher affinity of the syn isomer for PBPs, however, may also be a factor.

  28. Non-typical β-Lactam antibiotics and inhibitors of β-lactamase The carbapenem, penem, oxypenam, monobactam, belong to non-typical β-Lactam antibiotics .

  29. β-lactamase is produced by bacteria, which catalyse the hydrolysis of β-lactams. There are about fifty different known types. The production of β-lactamases by bacterial cells is the most important contributing factor to the development of penicillin-resistant strains of bacteria.

  30. Sulbactam (舒巴坦,青霉烷砜) (2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-bicyclo[3.2.0]heptane-2-carboxylic acid –4,4-dioxide Sulbactam is a irreversible inhibitor of β-Lactamase. It is active for neither G-N nor G-P. Combination with Ampicillin (1:2) to form the pro-drug Sultamicillin(舒它西林） Sultamicillin

  31. Synthesis

  32. Aztreonam(氨曲南 ） • Aztreonam is a monobactam prepared by chemically total synthesis. It binds with high affinity to PBPs in Gram-negative bacteria only. It is inactive against Gram-positive bacteria and anaerobes.

  33. Clavulanic Acid (克拉维酸,棒酸) (Z)-(2S,5R)-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-bicyclo[3.2.0]heptane-2-carboxylic acid Clavulanic acid, fementating from Streptomyces Clavuligerus. is an β-Lactamase inhibitor combination with other antibiotics, the combination with amoxicillin is active for amoxillin-resistance bacteria.

  34. Mechanism of action

  35. Summary • Cephalosporins • Four generations of cephalosporins • Non-typical β-Lactam antibiotics and inhibitors of β-lactamase Typical Drugs: Cephalexin, Cefotaxime Sodium Clavulanic Acid

  36. Assignment: • 1.Read textbook pp319-334 • 2.Do homework: Exercises of medicinal chemistry p84 Type A and 药物化学学习指导,第八章

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