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 [Link]
Software: 1. ChemDraw 12;

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