Cephalosporins: Structure and Modifications
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Questions and Answers

What is the basic nucleus of cephalosporins?

  • Bicyclic system
  • Penicillins
  • 7-ACA (correct)
  • b-Lactam ring

What is the crucial component of the mechanism of cephalosporins?

  • Acetoxy substituent
  • Stereochemistry
  • Carboxylic acid at position 4
  • b-Lactam ring (correct)

What is the importance of the carboxylic acid at position 4?

  • Important to binding (correct)
  • Increases ring strain
  • Helps in fermentation
  • Not important to the mechanism

What is essential for high acid stability and good oral activity of cephalosporins?

<p>Absence of the leaving group at the 3-position (D)</p> Signup and view all the answers

What is the limitation of generating analogues of cephalosporins?

<p>Cannot be generated by fermentation or full synthesis (B)</p> Signup and view all the answers

Why is cephaloglycin poorly absorbed orally despite having a phenylglycyl side chain?

<p>Due to solvolysis of the 3-acetoxyl group in the low pH of the stomach (C)</p> Signup and view all the answers

What is the role of the acetoxy group in the mechanism of cephalosporins?

<p>Acts as a good leaving group (D)</p> Signup and view all the answers

What happens to the 3-hydroxyl derivative under acidic conditions?

<p>It forms a lactone (A)</p> Signup and view all the answers

What is the reason for oral activity conferred by the phenylglycyl substituent?

<p>Increases acid stability of the lactam ring (B)</p> Signup and view all the answers

What is the importance of the bicyclic system in cephalosporins?

<p>Increases ring strain (C)</p> Signup and view all the answers

How do the in vitro antibacterial potencies of acyl derivatives of 7-ADCA compare to those of the corresponding 7-ACA analogs?

<p>The acyl derivatives have lower potencies (B)</p> Signup and view all the answers

What is a characteristic of cephalosporins compared to ampicillin?

<p>They are more resistant to inactivation by β-lactamases (B)</p> Signup and view all the answers

What is the significance of the 7-acylamino side chain?

<p>Important to the mechanism (D)</p> Signup and view all the answers

Why are cephalosporins considered broad-spectrum antibiotics?

<p>Due to their patterns of antibacterial effectiveness comparable to ampicillin (A)</p> Signup and view all the answers

What is the purpose of the protecting group in the generation of 7-ACA?

<p>To protect the 7-amino group (D)</p> Signup and view all the answers

What is the property of the bicyclic cephem ring system that contributes to the resistance of cephalosporins to β-lactamases?

<p>Its ability to resist hydrolysis by β-lactamases (D)</p> Signup and view all the answers

What is the result of hydrolysis of the secondary amide in the presence of a labile b-lactam ring?

<p>Generation of 7-ACA (D)</p> Signup and view all the answers

How do different cephalosporins vary in their susceptibility to hydrolysis by staphylococcal β-lactamase?

<p>They exhibit considerable variation in rates of hydrolysis (C)</p> Signup and view all the answers

What is the main advantage of first-generation cephalosporins over penicillin G?

<p>Reduced risk of allergic reactions (D)</p> Signup and view all the answers

Which of the following is a characteristic of first-generation cephalosporins?

<p>Resistance to penicillinase (C)</p> Signup and view all the answers

What is the main difference between first-generation and second-generation cephalosporins?

<p>Spectrum of activity against Gram-negative bacteria (B)</p> Signup and view all the answers

Which of the following is an example of a fourth-generation cephalosporin?

<p>Cefepime (B)</p> Signup and view all the answers

What is the structure of a first-generation cephalosporin?

<p>Has a side chain with a carboxyl group (D)</p> Signup and view all the answers

Which of the following is not a characteristic of first-generation cephalosporins?

<p>Highly active against Pseudomonas aeruginosa (A)</p> Signup and view all the answers

What is the main reason why Pseudonomas aeruginosa is administered by injection?

<p>It is poorly absorbed from the gut (C)</p> Signup and view all the answers

What happens to Cephalothin during metabolism?

<p>It undergoes deacetylation to give a 3-hydroxymethyl group (B)</p> Signup and view all the answers

Why is the pyridine ring in Cephaloridine a good leaving group?

<p>Because it is neutralized by a charge (C)</p> Signup and view all the answers

Why is Cefalexin administered orally?

<p>Because the methyl group at position 3 aids oral absorption (D)</p> Signup and view all the answers

What is the effect of the methyl group at position 3 in Cefalexin?

<p>It decreases activity but aids oral absorption (D)</p> Signup and view all the answers

What is the function of the hydrophilic amino group in Cefalexin?

<p>It helps to compensate for the loss of activity due to the methyl group (C)</p> Signup and view all the answers

Which of the following is a characteristic of Cefuroxime?

<p>It is resistant to esterases (D)</p> Signup and view all the answers

What is the main advantage of Cefuroxime over other cephalosporins?

<p>It has a wider spectrum of activity (D)</p> Signup and view all the answers

What is the main reason why Cefuroxime is useful?

<p>It is active against organisms that have gained resistance to penicillin (D)</p> Signup and view all the answers

Which of the following is NOT a characteristic of First Generation Cephalosporins?

<p>They are highly toxic (C)</p> Signup and view all the answers

Which of the following cephalosporins is used clinically against respiratory infections?

<p>Cefuroxime (D)</p> Signup and view all the answers

What is the characteristic of the aminothiazole ring in cephalosporins?

<p>Enhances penetration of cephalosporins across the outer membrane of Gram-negative bacteria (A)</p> Signup and view all the answers

Which of the following is an oral cephalosporin?

<p>Cefuroxime axetil (C)</p> Signup and view all the answers

What is the activity of third-generation cephalosporins against P. aeruginosa?

<p>Variable (C)</p> Signup and view all the answers

What is the characteristic of second-generation cephalosporins?

<p>Greater Gram-negative spectrum and resistant to beta-lactamase (A)</p> Signup and view all the answers

Which of the following is an injectable cephalosporin?

<p>Ceftazidime (D)</p> Signup and view all the answers

Study Notes

Cephalosporins

  • Naturally occurring cephalosporin is cephalosporin C
  • Semisynthetic modifications of the basic 7-ACA nucleus have resulted in useful antibiotics
  • The 7-amino group can be acylated with different acids or undergo nucleophilic substitution or reduction of the acetoxyl group

SAR of Cephalosporins

  • The beta-lactam ring is crucial to the mechanism of action
  • The carboxylic acid at position 4 is important for binding
  • The bicyclic system is important in increasing ring strain
  • Stereochemistry is important
  • The acetoxy substituent is important to the mechanism

Possible Modifications

  • 7-Acylamino side chain
  • 3-Acetoxymethyl side chain
  • Substitution at C-7

Generation of 7-ACA

  • Not possible to generate analogues by fermentation
  • Not possible to generate analogues by full synthesis
  • Restricted to semi-synthetic procedure
  • Need to hydrolyze a relatively unreactive secondary amide in the presence of a labile beta-lactam ring

Mechanism of Action

  • The acetoxy group acts as a good leaving group and aids the mechanism
  • The beta-lactam ring is crucial to the mechanism
  • The carboxylic acid at position 4 is important for binding

Oral Cephalosporins

  • The oral activity conferred by the phenylglycyl substituent is attributed to increased acid stability of the lactam ring
  • The absence of the leaving group at the 3-position is important for high acid stability and good oral activity
  • The 3-hydroxyl derivatives and, especially, the corresponding lactones are considerably less active in vitro than the parent cephalosporins

Spectrum of Activity

  • The cephalosporins are considered broad-spectrum antibiotics with patterns of antibacterial effectiveness comparable to that of ampicillin
  • Cephalosporins are much more resistant to inactivation by beta-lactamases than ampicillin
  • Ampicillin is generally more active against non-beta-lactamase-producing strains of Gram-positive and Gram-negative bacteria sensitive to both it and the cephalosporins

Beta-Lactamase Resistance

  • The susceptibility of cephalosporins to various lactamases varies considerably with the source and properties of these enzymes
  • Cephalosporins are significantly less sensitive than all but the beta-lactamase-resistant penicillins to hydrolysis by the enzymes from S. aureus and Bacillus subtilis
  • The "penicillinase" resistance of cephalosporins appears to be a property of the bicyclic cephem ring system rather than of the acyl group

Classification of Cephalosporins

  • First-generation cephalosporins: Cephalothin, Cefaloridine
  • Second-generation cephalosporins: Cefuroxime, Cefaclor, Cefprozil
  • Third-generation cephalosporins: Cefotaxime, Ceftazidime, Cefixime
  • Fourth-generation cephalosporin: Cefepime

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Description

Learn about the structure of cephalosporins, including the basic 7-ACA nucleus and its semisynthetic modifications through acylations and nucleophilic substitution.

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