Chapter 8 Antibiotics Section 1. ߖLactam Antibiotics(2)

1
Chapter 8 AntibioticsSection 1. ßLactam
Antibiotics(2)

• Wei-Min Chen, Prof.
• Department of Medicinal Chemistry, JNU

2
Topics in This Class

• Cephalosporins
• Non-typical ß-lactam antibiotics and inhibitors
  of ß-lactamase
• Tetracyclines
• Key drugs Cephalosporins ,Cephalexin, Cefotaxime
  Sodium
• Tough issues inhibitors of ß-lactamase

3
Cephalosporins
4

• The cephalosporins are a subgroup of ßlactam
  antibiotics, whose bicyclic system, called the
  cepham nucleus, consists of a four-member
  ßlactam 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
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 ß -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
ß-Lactamase III S atom can be replaced by O- or
CH2-. IV Relating with the antibacterial
activity and bioavailability.
12
 

 

 

13
(No Transcript)
14
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 ß-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.

15
Structures of first-generation cephalosporins.
16
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 ß-lactamases.

 

17
The second-generation cephalosporins
18
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.

 
 

 


19
The third-generation cephalosporins
20
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.

 

 

21
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

 

 

22
Synthetic Methods of Semi-Cephalosprins
The preparation of 7-aminocephalospranic Acid
(7-ACA)
Method 1
23
(No Transcript)
24
Chemical Transformation of a Penicillin Nucleus
to a Cephalosporin Nucleus. The preparation of
7-amino-3-deacetoxycephalosporanic acid (7-ADCA)
25
(No Transcript)
26
1.Cephalexin (????,????,??IV?)  

• (6R,7R)-3-Methyl-7-(R)-2-amino-2-phenylacetylamin
  o-8-oxo-5-thia-1-azabicyclo4.2.0oct-2-ene-2-car
  boxylic acid monohydrate.

27
Discovery

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

28
(No Transcript)
29
Synthesis of Cephalexin
30
2.Cefotaxime Sodium(?????)
(6R,7R)-3-(Acetyoxy)methyl-7-(amino-4-thiazolyl
)-(methoxyimino) acetylamino-8-oxo-5-thia-1-azabi
cyclo 4.2.0oct-2-ene-2-carboxylic acid sodium
31
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 ßlactamase-producing bacterial strains are
  sensitive to cefotaxime.

32
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.

33
Non-typical ß-Lactam antibiotics and inhibitors
of ß-lactamase

• The carbapenem, penem, oxypenam, monobactam,
  belong to non-typical ß-Lactam antibiotics .

34
ß -lactamase is produced by bacteria, which
catalyse the hydrolysis of ß-lactams. There are
about fifty different known types. The
production of ß-lactamases by bacterial cells is
the most important contributing factor to the
development of penicillin-resistant strains of
bacteria.
35
Sulbactam (???,????)
(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-bicyclo3.2.0
heptane-2-carboxylic acid 4,4-dioxide
Sulbactam is a irreversible inhibitor of
ß-Lactamase. It is active for neither G-N nor
G-P. Combination with Ampicillin (12) to form
the pro-drug Sultamicillin(????)
Sultamicillin
36
Synthesis
37
Aztreonam(??? )

• 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.

38
Clavulanic Acid (????,??)
(Z)-(2S,5R)-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-
bicyclo3.2.0heptane-2-carboxylic acid
Clavulanic acid, fementating from Streptomyces
Clavuligerus. is an ß-Lactamase inhibitor
combination with other antibiotics, the
combination with amoxicillin is active for
amoxillin-resistance bacteria.
39
Mechanism of action
40
(No Transcript)
41
Summary

• Cephalosporins
• Four generations of cephalosporins
• Non-typical ß-Lactam antibiotics and inhibitors
  of ß-lactamase
• Typical Drugs
• Cephalexin,
• Cefotaxime Sodium
• Clavulanic Acid

42

• Assignment
• 1.Read textbook pp319-334
• 2.Do homework Exercises of medicinal chemistry
  p84 Type A and ????????,???