Penicillin Introduction Mechanism Classification Spectrum of activity Uses adverse effect. 2-Cephalosporin Introduction Mechanism of action Classification Spectrum of activity Uses Adverse effect.

1. β-Lactam Antibiotics
(Penicillins and Cephalosporins)
NasirAli
Lecturer Pharmaceutical Chemistry

2. Introduction to beta-lactams:
• The name “lactam” is given to cyclic amides
and is analogous to the name “lactone” which
is given to cyclic esters
• β-Lactam is a “cyclic amide” with four atoms
in its ring.

3. Introduction to beta-lactams:
• The “β-lactam” ring is the main part of
pharmacophore of these antibiotics.
• β-Lactam antibiotics include two major,
widely used classes of antibiotics
1) Penicillins
2) Cephalosporins

4. Introduction to beta-lactams:
• The penicillins subclass of β-lactam antibiotics
is characterized by the presence of substituted
5-membered thiazolidine ring fused to the β-
lactam ring
• This fusion and chirality of the β-lactam ring
results in the molecule roughly possessing a
“V-Shape"

5. Introduction to beta-lactams:
• This drastically interferes with the planarity of
lactam bond and inhibits resonance of the
lactam nitrogen with its carbonyl group
• Consequently, the beta-lactam ring is more
reactive and more sensitive to nucleophilic
attack compared to normal planar amides

7. PENICILLINS
• Discovered by Alexander Fleming in 1928
• Was isolated from fungus Penicillium notatum
which is now known as Penicillium chrysogenum
• Florey and Chain isolated penicillin through freeze
drying and chromatography
• Penicillin was effective even when is was diluted
to 800 times

14. Stability and SAR of Penicillins
• The chemical constituents attached to penicillin
nucleus can greatly influence the stability of the
penicillins and spectrum of activity
• Substitution of side chain R with an electron-
withdrawing group decreases the electron-density
on the side chain carbonyl and protects penicillins
from acid degradation.

15. Stability and SAR of Penicillins
• This property has clinical implication because
these compounds survive passage through the
stomach and can be given orally for systemic
activity
• In-vitro degradation of penicillins can be retarded
by keeping pH of solutions 6-6.8 and by
refrigerating them

17. Mechanism of action of penicillins

18. Mechanism of action of penicillins

19. Allergic reactions to Penicillins
• Allergy to penicillins is expressed as mild drug
rash or itching and is of delayed onset
• Occasionally the reaction is immediate and
profound
• It may include the cardiovascular collapse and
shock
• Topical wheal-and-flare test may be performed

20. Allergic reactions to Penicillins
• Erythromycin and clindamycin are useful
alternatives for therapy in many cases of penicillin
allergy
• Penicillins are prepared in facilities separate from
those used to prepare other drugs to prevent cross-
contamination and possible sensitization.

21. Allergic reactions to Penicillins
• The origin of allergy is hepatic reaction (formation of
antigenic penicilloyl proteins due to reaction of
nucleophilic group e.g. ε-Amino with β-lactam ring)
with host proteins and the responsible bond is in the
beta lactam ring
• Hence, this side effect is caused by the
pharmacophore and is unlikely to overcome with the
molecular manipulations.

22. Resistance to Penicillins
• The first mode of resistance is due to enzymatic
hydrolysis of the beta-lactam ring
• If the bacterium produces the enzymes beta-lactamase
or penicillinase, these enzymes will break open the
beta lactam ring rendering the antibiotic ineffective
• 2nd mode of beta-lactam resistance is due to possession
of altered penicillin-binding-proteins (PBPs)

23. Resistance to Penicillins
• Beta-lactams cannot bind effectively to these PBPs
as a result these antibiotics become less effective in
disrupting the cell wall
• Resistance to beta lactamase can be reduced by
carrying out some structural modifications in the
parent compound

24. Benzylpenicillin (Penicillin G)
Benzyl group

25. Benzylpenicillin (Penicillin G)
• Effective majorly against gram positive cocci but
also effective against Neisseria gonorrhoeae and
Haemophilus influenza
• Cheap, efficacious and less toxic
• Many formerly sensitive bacteria are now resistant
• Used in upper and lower RTIs, genitourinary tract
infections

26. Benzylpenicillin (Penicillin G)
• Effective route of administration is parenteral
• Penicillin G is unstable under acidic conditions of
stomach
• Need to improve defects in benzylpenicillin such as
comparative instability, poor oral absorption,
allergenicity, sensitivity to beta-lactamases and
relatively narrow antimicrobial spectrum

27. Phenoxymethyl penicillin (Penicillin V)
Phenoxy methyl group
More electronegative
O-atom inhibits β-lactam
bond hydrolysis

28. Phenoxymethyl penicillin (Penicillin V)
• Produced by bacteria in a medium rich in phenoxy
acetic acid
• Can also be prepared by semi-synthesis and is
comparatively more stable than penicillin G
• Stability is due to electronegative oxygen atom at
C-7 amide side chain inhibiting participation in
beta-lactam bond hydrolysis

29. Phenoxymethyl penicillin (Penicillin V)
• It was the first oral penicillin
• Antimicrobial spectrum is roughly same as that of
penicillin G
• Not used for acutely severe infections
• Same sensitivity to beta-lactamases as penicillin G
and almost same allergenicity

30. Methicillin
Dimethoxy benzoyl group

31. Methicillin
• Although it is not used today but methicillin was
first penicillinase resistant penicillin used clinically
• Unstable in gastric acid (half life = 5 min at pH = 2)
• Increased bulk resulting from the addition of
dimethoxybenzoyl group to 6-APAleads to
methicillin (beta-lactamase resistant)

32. Methicillin
• Methicillin has significantly narrower antimicrobial
spectrum so it was limited to use clinically only for
infections caused by beta-lactamase producing
Staphylococcus aureus and few other infections
• MRSA refers to methicillin resistant staphylococcus
aureus
• Resistance mechanism includes altered PBPs

33. Methicillin
• Methicillin is also an effective inducer of
penicillinases
• Methicillin has now been supplemented by a
number of agents

34. Oxacillin, Cloxacillin and Dicloxacillin

35. Oxacillin, Cloxacillin and Dicloxacillin
• They differ with reference to position of chlorine on
benzene ring
• They are somewhat more acid-stable with almost
same antimicrobial spectrum
• They do not cause production of beta-lactamase but
show activity against those bacteria who do produce
beta-lactamases

36. Oxacillin, Cloxacillin and Dicloxacillin
• Can be taken orally and are more potent
• Highly serum protein bound
• Not good choice for treatment of septicemia
• Microbes resistant to methicillin are also resistant to
isoxazolyl group of penicillins
• Used against Staphylococcus aureus

37. CEPHALOSPORINS
• These are beta lactam antibiotics isolated from
cephalosporium sp. and/or prepared synthetically
• These are in fact 7-cephalosporanic acid (7-ACA)
derivatives
• More acid-labile than corresponding 6-APAderivatives
• Mechanism of action is similar to penicillins i.e they
inhibit the cross-linking of peptidoglycan by inhibiting
the transpeptidase

38. Cephalosporin C

39. CEPHALOSPORINS
• 7-ACA was derived from cephalosporin C and was
proved to be analogous to penicillin nucleus 6-APA
but was not sufficiently potent to be used clinically
• Modifications of 7-ACA produced useful antibiotic
agents
• First agent cephalothin was launched by Eli Lilly in
1954

42. General Structure of cephalosporin
Dihydrothiazine ring

43. Comparing cephalosporins and penicillins

48. Degradation of cephalosporins
• Cephalosporins are more stable than penicillins
• Still undergo a variety of transformations
• The nature of reaction depends upon the side chain at
C-7 and substitution on C-3
• The presence of a good leaving group at C-3 facilitates
spontaneous expulsion of 3-subsituent either due to
hydrolysis of C-N bond of β-Lactam ring or by any
general nucleophile.

49. Degradation of cephalosporins
• Thus, desacetyl cefotaxime is more stable to hydrolysis than
cefotaxime
• absence of a good leaving group at C-3 makes them more
acid labile and makes them suitable for oral consumption
• Hence, cephalexin having methyl group at C-3 is much better
absorbed orally than cephaloglycin having acetoxymethyl
group at C-3 while both have same phenylglycyl side chains
at C-7

50. Degradation of cephalosporins
• The nature of substituent at C-7 determines the
facility with which the β-Lactam bond is
hydrolyzed or broken either by chemical or
enzymatic means of degradation of cephalosporin C

51. Effect of acids on cephalosporins
• In the presence of esterase/acid, cephalosporin C givesdesacetyl
cephalosporin and then inactive desacetyl cephalosporinlactone

52. Effect of β-lactamase on cephalosporins
β-lactamase or cephalosporanase degraded cephalosporin C into
cephalosporoic acid, anhydrodesacetyl cephalosporoic acid and
desacetyl cephalosporoic acid

53. Effect of acylase on cephalosporins
Cephalosporin gives 7-aminocephalosporanic acid which in the presence
of acid undergoes lactonization to produce inactive inactive desacetyl-7-
amino cephalosporanic acid lactone

54. Acylation inc. g+ve
antibacterial activity but
reduces g-ve activity
Phenyl ring can be
replaced by
thiophene, tetrazole,
furan, pyridine and it
increases activity
C-3 susbsituent
affects pKinetics.
Modifications can
be done to reduce
degradation

55. Cefazolin
• Natural acetyl side chain is replaced by thio-linked
thiadiazole ring
• Although above group is good leaving group the drug is not
subjected to hydrolysis
• At C-7 is possesses tetrazoylmethylene unit
• Less irritant on injection and has longer half life
• It is comparatively unstable and should be protectedfrom
heat and light

56. Cephalexin
• It contains ampicillin-type side chain and therefore is orally
active but does not cause any antimicrobial shift in activity
• Not any activating side chain at C-3 and is less potent
• Does not undergo deactivation and thus maintains potency
• Rapidly and completely absorbed from GIT
• More effective against gram+ve and less effective against gram-
ve bacteria just like other 1st generation cephalosporins

57. Cefadroxil
• It contains amoxicillin-type side chain and is orally
active
• Cefadroxil has some immunostimulant properties
mediated through T-cell activation which may benefit
patients fighting infections
• Prolonged half-life allows once daily dosing

58. Cefradine
• The aromatic ring in the ampicillin side chain has been partially
hydrogenated by a Birch reduction such that the resulting molecule is
still planar and л-electrons excessive but has no conjugated oleifinic
linkages
• It is comparatively acid-stable (completely absorbed from GIT)
• It can be given IM as well as orally
• Due to some other reasons, IV and IM forms of cephradine are not
available in United States

59. • Cefamandole nafate has formylated D-mandelic amide moiety at
C-7
• The formate ester is cleaved rapidly in the host to release the more
active cefamandole
• The esterification also apparently overcomes the instability of
cefamandole when it is stored in dry form
2ND GENERATION CEPHALOSPORINS
Cefamandole

60. • This agent has increased activity against Haemophilus
influenza and some gram negative bacilli as compared with
1st generationcephalosporins
• Loss of 5-thiol-1-methyl-1-H-tetrazole moiety (sometimes
referred as MTT) from C-3 is associated with prothrombin
deficiency and bleeding problems as well as anAntabuse-like
acute alcohol intolerance
Cefamandole

61. • This group also enhances potency and prevents metabolism by
deacetylation
• Like other 2nd generation cephalosporins, cefamandole is more
active against gram negative bacteria
• Principle clinical use is for lower respiratory tract infections as
well as septicemia and UTIs, skin and skin structures, bone and
joint infections.
Cefamandole

62. • Has an unesterified D-mandelic acid moiety at
C-7 and a methylsulfothiotetrazole group at C-3
• The latter is related to MTT moiety mentioned
above in cefamandole nafate
• However, the clotting problems andAntabuse-
like side effects associated with MTT has not
been reported with cefonicid
• The extra acid group at C-3 side chain makes
possible to sell it as injectable disodium salt.
Cefonicid

63. • Pain and discomfort at injection site is experienced by
some of the patients
• Cefonicid has longer half-life than the other members
of this group
• The drug is somewhat unstable needs to be protected
from heat and sunlight and may yellow or darken
Cefonicid

64. • Kirby-Bauer disk testing may overestimate the
beta-lactamase producing bacteria to this agent, so
some extra precaution in interpretation of
laboratory results is required.
Cefonicid