study of natural products (cephalosporins and carbapenems) as a lead for new pharmaceuticals

1. BETA-LACTAM
ANTIBIOTICS
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2. CONTENTS:
• Introduction
• Cephalosporins: History
Chemistry
Structural activity relationship
Classification
Generations
• Carbapenems: Structure
Effect on activity
classification
• Reference
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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
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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.
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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.
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6. CEPHALOSPORIN C
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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

10. STRUCTURAL ACTIVITY RELATIONSHIP
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11. GENERATIONS
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12. CLASSIFICATION:
GENERATION
ROUTE OF
ADMINISTRATION
EXAMPLES
1st Generation Oral Cephadrine,Cephalaxin
Parenteral Cephazolin,Cephalothin
2nd Generation
Oral Cefaclor,Cefprozil
Parenteral Cefuroxime,Cefoxitin
3rd Generation
Oral Cefixime,Ceftibutin
Parenteral Ceftriaxone,Cephatoxime
4th Generation
Oral ---
Parenteral Cefipime,Cefpirome
5th Generation
Oral ---
Parenteral Ceftaroline,Ceptobiprole
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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.

14. ADVERSE EFFECTS
Allergic Reactions
Nephrotoxicity
Diarrhoea
Disulfiram like Reaction
Bleeding Disorder
Superinfections

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.
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7 6
5
3
2
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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.
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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
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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
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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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