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</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</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</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</p> Signup and view all the answers

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

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

    What is the importance of the bicyclic system in cephalosporins?

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

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

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

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

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

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

    <p>Cefepime</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</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</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</p> Signup and view all the answers

    What happens to Cephalothin during metabolism?

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

    Why is Cefalexin administered orally?

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

    Which of the following is a characteristic of Cefuroxime?

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

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

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

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

    <p>Cefuroxime</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</p> Signup and view all the answers

    Which of the following is an oral cephalosporin?

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

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

    <p>Variable</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</p> Signup and view all the answers

    Which of the following is an injectable cephalosporin?

    <p>Ceftazidime</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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