3. • β-Lactam antibiotics are the most widely produced and used antibacterial drugs in the world, and have
been ever since their initial clinical trials in 1941.
• β-Lactams are the antibiotics mainly acting by inhibiting the cell wall synthesis which has a basic
moiety of beta-lactum ring
Various beta lactum antibiotics available are:
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactums
Beta-lactam ring
INTRODUCTION
3
4. CEPHALOSPORINS
Cephalosporins are the second major
group of beta- lactum antibiotics broad
spectrum,penicillinase resistance
antibiotic that is derived from the
microorganism “Acronium crysogenum”
Cephalosporins are similar to penicillins
where they have a 6 membered
dihydrothiazine ring instead of a 5
member thiazolidine ring.
Unlike penicillin, cephalosporins have two
side chains which can be easily modified.
Cephalosporins are also more difficult for
β-lactamases to hydrolyze.
4
5. HISTORY
• Cephalosporins were discovered shortly after penicillin entered into widespread product, but not
developed till the 1960’s.
• Cephalosporins were first isolated from cultures of “Cephalosporins acremonium” from a sewer in
SARDINIA in 1945 by an Italian scientist GIUSEPPE BROTZU.
• He noticed that the cultures produced substances that were effective against Salamonella typhi.
• In 1948 Abraham and his colleagues have been supplied cultures of the fungus and was isolated
three principal antibiotic components:- Cephalosporin P, (a steroid antibiotic that resembles
fusidicacid) with minimal antibacterial activity, obtained from Fusidium coccineum.;CEPHALOSPORIN
N, later discovered to be identical with synnematin N (a penicillin derivative now called penicillin n)-it
was found to be the derivative of 6-amino penicillanic acid .It has greater activity against gram-ve
bacteria .
• Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins.
5
7. CHEMISTRY
• It has a bicyclic system containing 4- membered 𝜷 -
lactam ring fused to a six membered dihydrothiazine
ring system.
• Nucleus of the most cephalosporin is 7- amino-
cephalosporanic acid (7 aca) .
• The nucleus of cephalosporins, 7-
aminocephalosporanic acid bears a close
resemblance to 6-amino penicillanic acid.
• Modification of side chains on the relevant positions
has been used to create a whole new class of
cephalosporin antibiotics.
• Modification of side-chains at position 7 of the
lactam ring seems to affect the antibacterial activity
while position 3 of the dihydrothiazine ring alters
pharmacokinetic properties and receptor binding
affinity. 7
8. 1. SUBSTITUTION ON 7- ACYLAMINO:
Acylation of amino group increases the potency against
gram-positive bacteria, but it decreases gram-negative
potency.
• High antibacterial activity is observed only when new
acyl groups are derived from carboxylic acids for gram-
positive bacteria.
• Substituents on aromatic ring that increases
lipophilicity provide higher gram-positive activity and
lower gram-negative activity.
• Phenyl ring in side-chain can be replaced with other
heterocycles (like- minded thiophene, furan, pyrimidine
etc.) Which shows improved spectrum of activity &
Pharmacokinetic properties.
(1)
(2)
(3)
STRUCTURAL ACTIVITY RELATIONSHIP
9. 2. SUBSTITUTION ON C-3
• Nature of C-3 substituents influences pharmacokinetic & pharmacological properties as well
as antibacterial activity
• Modification at C-3 position has been made to reduce the degradation of cephalosporin.
3. Displacement of acetoxy group by azide ion yield derivatives which relatively low gram-
negative activity.
Displacement of 3-acetoxy group with thiols will enhance the activity against gram-negative
bacteria with improved pharmacokinetic properties.
• Replacement of ACETOXY group at position C-3 with -CH3,-Cl has resulted in orally active
compounds.
• Carboxyl group of position-4 has been converted into ester prodrugs to increase
bioavailability of cephalosporin & these can be given orally.
• Oxidation of ring sulphur to sulphoxide or sulphone greatly destroy the antibacterial activity.
• Replacement of sulphur with oxygen leads to oxacepham with increased antibacterial activity.
• Replacement of sulphur with methylene group has greater chemical stability & a longer half –
life.
STRUCTURAL ACTIVITY RELATIONSHIP
13. MECHANISM OF ACTION
Mechanism of Action Cephalosporins exert bactericidal effect in manner similar to that of
Penicillins. i.e., by:
Binding to specific PBPS,
Inhibition of cell wall synthesis by inhibiting transpeptidation of Peptidoglycan,
Activation of Autolytic enzymes Autolysins or Murein Hydrolases.
16. CARBAPENEMS
• Carbapenems are a class of beta-lactam antibiotics with
a broad spectrum of antibacterial activity.
• They have a structure that renders them highly resistant
to betalactamases.
• Carbapenem antibiotics were originally developed from
thienamycin, a naturally-derived product of Streptomyces
cattleya.
• This class of antibiotics is usually reserved for known or
suspected multidrug-resistant (MDR) bacterial infections
• Carbapenems are typically unaffected by
emerging antibiotic resistance, even to other beta-
lactams.
• Carbapenem antibiotics were originally developed
at Merck & Co. from the carbapenem thienamycin,a
naturally derived product of Streptomyces cattleya
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17. STRUCTURE :
• The sulfur atom is not part of the 5-
membered ring but, rather, has been
replaced by a methylene moiety at that
position.
• The carbapenem ring system very
susceptible to reactions cleaving the β-
lactam bond.
• At C-6, there is a 2-hydroxyethyl group
attached with α-stereochemistry.
• Thus, the absolute stereochemistry of the
molecule is 5R,6S,8S.
• The endocyclic olefinic linkage also
enhances the reactivity of the β-lactam ring.
18
7 6
5
3
2
17
18. EFFECTS ON ACTIVITY
• Has extremely intense and broad-spectrum antimicrobial activity as well as
• Inactivates β-lactamases
• Hence molecule has the functional features of the best of the β-lactam antibiotics
as well as the β-lactamase inhibitors.
• Consequently, the carbapenem ring system is highly strained and very
susceptible to reactions cleaving the β-lactam bond.
18
19. • THIENAMYCIN:first of the
carbapenems,Isolated from Streptomyces
cattleya.The terminal amino group in the
side chain attached to C-3 is nucleophile
and attacks the β-lactam bond of a nearby
molecule through an intermolecular react
ion destroying activity
• IMIPENEM:Imipenem is very stable to
most –lactamases however Inhibitory to
many β-lactamases.Imipenem is not orally
active.The more common adverse effects
are irritation at the infusion site, nausea,
vomiting, diarrhea, and pruritus.
THIENAMYCIN
IMIPENEM
19
20. • MEROPENEM: II generation, orally inactive -
most extensive clinical evaluation.It exhibits
greater potency against Gram-negative and
anaerobic bacteria than does imipenem, but it
is slightly less active against most Gram-
positive species. It is not effective against
MRSA.Meropenem is not hydrolyzed by DHP-
I and is resistant to most -lactamases,
including a few carbapenemases that
hydrolyze carbapenem
MEROPENEM
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21. • DORIPENEM:Doripenem is the newest of
the approved carbapenems.It also contains
the 4-β-methyl group, which confers stability
toward dehydropeptidase-1, so it is given as
a single agent.
• ERTAPENEM:Ertapenem is another
synthetic carbapenem with a rather complex
side chain at C-3.As with meropenem and
doripenem, the 4-β-methyl group confers
stability toward dehydropeptidase-1.
DORIPENEM
ERTAPENEM
21
22. ADVERSE EFFECTS:
Serious and occasionally fatal allergic reactions can
occur in people treated with carbapenems.
Seizures are a dose-limiting toxicity for both
imipenem and meropenem.
Clostridium difficile-related diarrhea may occur in
people treated with carbapenems or other broad
spectrum antibiotics.
Those with an allergy to penicillin may develop a
cross sensitivity to carbapenems.
23. REFERENCE
• https://en.wikipedia.org/
• https://www.researchgate.net/
• Wilson and Gisvold's Textbook of
Organic Medicinal and Pharmaceutical Chemistry, 12th
Edition. by John M. Beale & John Block. ― Gordana
Biernat.
• Principles of Medicinal Chemistry, 4th Edition Edited by
William O. Foye, Thomas L. Lemke, and David A. Williams.
Williams and Wilkins, Philadelphia, PA. 1995
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