40 Questions
What is the basic nucleus of cephalosporins?
7-ACA
What is the crucial component of the mechanism of cephalosporins?
b-Lactam ring
What is the importance of the carboxylic acid at position 4?
Important to binding
What is essential for high acid stability and good oral activity of cephalosporins?
Absence of the leaving group at the 3-position
What is the limitation of generating analogues of cephalosporins?
Cannot be generated by fermentation or full synthesis
Why is cephaloglycin poorly absorbed orally despite having a phenylglycyl side chain?
Due to solvolysis of the 3-acetoxyl group in the low pH of the stomach
What is the role of the acetoxy group in the mechanism of cephalosporins?
Acts as a good leaving group
What happens to the 3-hydroxyl derivative under acidic conditions?
It forms a lactone
What is the reason for oral activity conferred by the phenylglycyl substituent?
Increases acid stability of the lactam ring
What is the importance of the bicyclic system in cephalosporins?
Increases ring strain
How do the in vitro antibacterial potencies of acyl derivatives of 7-ADCA compare to those of the corresponding 7-ACA analogs?
The acyl derivatives have lower potencies
What is a characteristic of cephalosporins compared to ampicillin?
They are more resistant to inactivation by β-lactamases
What is the significance of the 7-acylamino side chain?
Important to the mechanism
Why are cephalosporins considered broad-spectrum antibiotics?
Due to their patterns of antibacterial effectiveness comparable to ampicillin
What is the purpose of the protecting group in the generation of 7-ACA?
To protect the 7-amino group
What is the property of the bicyclic cephem ring system that contributes to the resistance of cephalosporins to β-lactamases?
Its ability to resist hydrolysis by β-lactamases
What is the result of hydrolysis of the secondary amide in the presence of a labile b-lactam ring?
Generation of 7-ACA
How do different cephalosporins vary in their susceptibility to hydrolysis by staphylococcal β-lactamase?
They exhibit considerable variation in rates of hydrolysis
What is the main advantage of first-generation cephalosporins over penicillin G?
Reduced risk of allergic reactions
Which of the following is a characteristic of first-generation cephalosporins?
Resistance to penicillinase
What is the main difference between first-generation and second-generation cephalosporins?
Spectrum of activity against Gram-negative bacteria
Which of the following is an example of a fourth-generation cephalosporin?
Cefepime
What is the structure of a first-generation cephalosporin?
Has a side chain with a carboxyl group
Which of the following is not a characteristic of first-generation cephalosporins?
Highly active against Pseudomonas aeruginosa
What is the main reason why Pseudonomas aeruginosa is administered by injection?
It is poorly absorbed from the gut
What happens to Cephalothin during metabolism?
It undergoes deacetylation to give a 3-hydroxymethyl group
Why is the pyridine ring in Cephaloridine a good leaving group?
Because it is neutralized by a charge
Why is Cefalexin administered orally?
Because the methyl group at position 3 aids oral absorption
What is the effect of the methyl group at position 3 in Cefalexin?
It decreases activity but aids oral absorption
What is the function of the hydrophilic amino group in Cefalexin?
It helps to compensate for the loss of activity due to the methyl group
Which of the following is a characteristic of Cefuroxime?
It is resistant to esterases
What is the main advantage of Cefuroxime over other cephalosporins?
It has a wider spectrum of activity
What is the main reason why Cefuroxime is useful?
It is active against organisms that have gained resistance to penicillin
Which of the following is NOT a characteristic of First Generation Cephalosporins?
They are highly toxic
Which of the following cephalosporins is used clinically against respiratory infections?
Cefuroxime
What is the characteristic of the aminothiazole ring in cephalosporins?
Enhances penetration of cephalosporins across the outer membrane of Gram-negative bacteria
Which of the following is an oral cephalosporin?
Cefuroxime axetil
What is the activity of third-generation cephalosporins against P. aeruginosa?
Variable
What is the characteristic of second-generation cephalosporins?
Greater Gram-negative spectrum and resistant to beta-lactamase
Which of the following is an injectable cephalosporin?
Ceftazidime
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
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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