Medicinal Chemistry IV Antibiotics: Cephalosporins

CHAPTER 2:
ANTIBIOTICS: BETA-LACTAMS: CEPHALOSPORINS
Sam Dawbaa, Pharm. Chem. Ph.D.

A. MECHANISM OF ACTION: .
Similar to Penicillins.

B. NOMENCLATURE & SEMISYNTHESIS .

The β-lactam ring of cephalosporins is fused with a six-membered dihydrothiazine ring (while
penicillins have a five-membered thiazolidine ring). This 6-membered ring make less strain on the β-
lactam part which lead to less reactivity or potency. 7-Aminocephalosporanic acid (7-ACA) in
cephalosporins is the equivalent to 6-aminopenicillanic acid (6-APA) in penicillins.

7-ACA cannot be obtained by fermentation

from the Cephalosporium acremonium fungi
neither by hydrolysis of cephalosporin C. Thus,
a special way was found to synthesis 7-ACA. 7-
ACA is then used in the synthesis of various
cephalosporin derivatives.

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 Medicinal Chemistry IV Antibiotics: Cephalosporins

C. SAR OF CEPHALOSPORINS

D. PROBLEMS OF CEPHALOSPORINS .
1. BACTERIAL RESISTANCE TO CEPHALOSPORINS
Susceptible cephalosporins can be hydrolyzed by β-lactamases. Certain β-lactamases are
constitutive (chromosomally encoded) in certain strains of gram-negative bacteria (Citrobacter,
Enterobacter, Pseudomonas, and Serratia) and are normally repressed. These are induced (or
derepressed) by certain β-lactam antibiotics (e.g., imipenem, cefotetan, and cefoxitin). Steric bulky
groups near the side-chain amide linkage can inhibit hydrolysis by the enzyme. Penetration barriers to
the cephalosporins are also known.

2. CHEMICAL DEGRADATION
• The most reactive group is the 3-acetoxylmethyl side chain. It undergoes nucleophilic
displacement reactions to give various products and solvolysis in strong acids to give the
desacetylcephalosporins which in turn forms lactones (inactive).
• 7-acylamino side chain can be hydrolyzed enzymatically (acylase) or nonenzymatically to
give 7-ACA or 7-aminodesacetylcephalosporanic acid (7-ADCA).
• β-lactam ring can be hydrolyzed similar to penicillins.

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 Medicinal Chemistry IV Antibiotics: Cephalosporins

3. ALLERGENICITY

• Allergenicity is less commonly experienced and is less severe with cephalosporins.

• Patients who have had a rapid and severe reaction to penicillins should not be treated with
cephalosporins.

E. CLASSIFICATION & PRODUCTS .

• Cephalosporins are divided into 4 generations (or 5) based on the time of discovery and
their antibacterial properties e.g., spectrum and resistance to β-lactamase.
• Individual cephalosporins differ in their pharmacokinetic properties, especially plasma
protein binding and half-life, but the structural bases for these differences are not obvious.

1. FIRST-GENERATION CEPHALOSPORINS .

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Medicinal Chemistry IV Antibiotics: Cephalosporins

• They are active in vitro against gram-positive cocci (penicillinase-positive and -negative
Staphylococcus aureus and Staphylococcus epidermis), group A β-hemolytic streptococci
(Streptococcus pyogenes), group B streptococci (Streptococcus agalactiae), and
Streptococcus pneumoniae.
• They are not effective against MRSA.
• They are not significantly active against gram-negative bacteria, although some strains of
Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Shigella sp. may be
sensitive.
1. CEFAZOLIN
o Cefazolin has a thio-linked thiadiazole ring which is an activating leaving group.
o At C-7, it possesses a tetrazoylmethylene unit. Its dosing should be reduced in the presence
of renal impairment.
o It is comparatively unstable and should be protected from heat and light.
2. CEPHALEXIN
o The side chain → oral activity to cephalexin.
o 3-methyl →↓ pontecy, ↓ metabolism → longer DOA.
o Orally absorbed completely.
3. CEFADROXIL
o Cefadroxil has an amoxicillin-like side chain at C-7 and is orally active.
o The prolonged biologic half-life of cefadroxil allows for once-a-day dosage.

2. SECOND-GENERATION CEPHALOSPORINS .

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Medicinal Chemistry IV Antibiotics: Cephalosporins

• The second-generation cephalosporins generally retain the anti–grampositive activity of the

first-generation agents but include Haemophilus influenzae as well and add to this better
anti–gram-negative activity, so that some strains of Acinetobacter, Citrobacter,
Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, Providencia, and Serratia are also
sensitive.
• Cefotetan and cefoxitin also have antianaerobic activity as well.
• Cefoxitin is useful against gonorrhea. It induces β-lactamase.
• Cefaclor 3-Cl group →↓ metabolism
• Some include N-methyl-5-thiotetrazole (MTT) at the C-3 position:
o The loss of this group by metabolism is associated with prothrombin deficiency
and bleeding problems.
o Also, it causes disulfiram-like acute alcohol intolerance.
o It enhances the potency.

3. THIRD-GENERATION CEPHALOSPORINS .

• The third-generation cephalosporins are less active against staphylococci than the first-
generation agents but are much more active against gram-negative bacteria than either the
first- or the second-generation drugs.
• They are useful against nosocomial multidrug-resistant hospital-acquired strains.
Morganella sp. and Pseudomonas aeruginosa can also be added to the list of species that
are often sensitive.

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Medicinal Chemistry IV Antibiotics: Cephalosporins

• Cefotaxime, like cefuroxime, has a Z-methoxyimino moiety at C-7 that conveys significant
β-lactamase resistance.
• In ceftizoxime, the whole C-3 side chain has been omitted to prevent deactivation by
hydrolysis.
• Ceftriaxone:
o the C-3 side chain consists of a metabolically stable and activating
thiotriazinedione in place of the normal acetyl group.
o It is useful for many severe infections and notably in the treatment of some
meningitis infections caused by gram-negative bacteria.
• Ceftazidime:
o Its 7-side chain causes stronger stability to β-lactamase, greater anti–Pseudomonas
aeruginosa activity, and increased activity against gram-positive organisms.
o The 3-pyridinium →↑ water solubility & activates the β-lactam ring.
o It is not stable in the presence of aminoglycosides and vancomycin.
• Cefixime has a 3-vinyl which enhances oral activity. It is poorly active against
staphylococci.

4. FOURTH-GENERATION CEPHALOSPORINS .

• The fourth-generation cephalosporins have an antibacterial spectrum like the third-

generation drugs but add some enterobacteria that are resistant to the third-generation
cephalosporins.
• They are also more active against some gram-positive organisms.
• Cefepime:
o contains a Z-methoxyimine moiety and an aminothiazolyl group at C-7, broadening
its spectrum, increasing its β-lactamase stability, and increasing its
antistaphylococcal activity.
o The quaternary N-methylpyrrolidine group at C-3 seems to help penetration into
gram-negative bacteria.
• The fourth generation cephalosporins are characterized by enhanced antistaphylococcal
activity and broader anti–gram-negative activity than the third-generation group. Cefepime

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Medicinal Chemistry IV Antibiotics: Cephalosporins

is used intramuscularly and intravenously against urinary tract infections, skin and skin
structure infections, pneumonia, and intra-abdominal infections.

Dr. Sam Dawbaa, Pharm. Chem. Ph.D. References:

1. Wilson & Gisvold’s, Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th edn.
2. Patrick’s, An Introduction to Medicinal Chemistry
3. Foye’s Principles of Medicinal Chemistry, 7th edn.
4. Akgun, Farmasötik Kimya
5. Pubchem https://pubchem.ncbi.nlm.nih.gov
Software: 1. ChemDraw 12;

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