NTA Level 5 • Semester 1 • PST05106

Structure – Activity Relationship of Cephalosporins

Pharmaceutical Organic Chemistry • Source Session/Topic 27

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Session 27: Structure – Activity Relationship of Cephalosporins.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

• Define Cephalosporins

• Explain Chemical structure of cephalosporins

• Explain the structure – activity relationship of cephalosporins

Resources Needed:

• Flip charts, marker pens, and masking tape.

• Black/white board and chalk/whiteboard markers.

SESSION OVERVIEW

SESSION CONTENTS.

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes).

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Definition of Cephalosporins (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Cephalosporins? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the table below |

• Cephalosporins are Antibacterial agents which inhibit bacterial cell

wall synthesis.

• Cephalosporins are the second group of β-lactam antibiotic family to be

discovered after penicillin, which showed broad spectrum of action

against Staphylococcus aureus, Vibrio cholerae, and B. anthracis, but

moderate antibacterial activity was isolated from the fermentation broth

of a strain of A. chrysogenum

• Cephalosporins are bactericidal antibiotics, chemically closely related

to penicillins, and have the same mode of action, disrupting the

synthesis of the peptidoglycan layer of bacterial cell walls of bacteria,

causing their death.

STEP 3: Chemical Structure of Cephalosporins (40 minutes).

• Cephalosporin is a β-lactam antibiotic that inhibits bacterial cell

wall synthesis.

• In 1948 Dr. Abraham first isolated cephalosporin C from a fungus

Cephalosporium acremonium.

• Cephalosporins have broader gram –ve coverage than penicillin yet no

one of the cephalosporins is active against MRSA and enterococci.

Basic structure of cephalosporin is 7-aminocephalosporanic acid

[pic]

Structural classification of cephalosparins

[pic]

STEP 4: Structure – Activity relationship of Cephalosporins (45 minutes).

|Activity: Small Group Discussion (20 minutes) |

| |

|DIVIDE students into small manageable groups. |

| |

|ASK students to discuss on the following question |

|What is the importance of SAR of Cephalosporins? |

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|ALLOW students to discuss for 15 minutes. |

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|ALLOW few groups to present and the rest to add points not mentioned. |

| |

|CLARIFY and SUMMARIZE by using the contents below |

Many analogues of Cephalosporin C have been made and the structure-activity

relationship (SAR) conclusions are as follows

• The β-lactam ring is essential

• A free carboxyl group is needed at position 4.

• The bicyclic system is essential

• The stereochemistry of the side-groups and the rings is important

These are very close to penicillin and there are only a limited number of

place where modifications can be made. Those places are:

• Variations of the 7-acylamino side chain

• Variations of the 3-acetoxymethyl side chain

• Extra substitution at carbon 7.

[pic]

Positions which can be varied

Beta-Lactam Ring:

• Required for PBP reactivity and antibacterial activity

• Reactivity reduced compared to the penicillins

• Compare mechanism of action, resistance, pharmacodynamics, etc to

penicillins

2-Carboxyl Group:

• Acidic: Salt formation, product formulation

• Prodrug formation

• Elimination profile: Renal

X-Substituent:

• Cephalosporins and cephamycins

• Determines, in part, resistance to beta-lactamase inactivation

3- Substituent (R3)

• Chemical/acid stability/instability

• Metabolic stability/instability

• Minimal impact on antibacterial activity

• Protein binding and half-life: Heterocycles

• Adverse Reaction and Drug Interaction

• Some role in cephalosporin classification (generation)

7-Substituent (R7)

• Incorporated by semi synthesis: Variable structures

• Impact on spectrum of activity (beta-lactamases, PBP affinity, etc.)

• Significant role in activity and classification by generation

Cephalosporin analogues

[pic]

• Different cephalosporins are developed by changing the moieties

attached at the 3 and/or 7 positions of the 7-ACA.

• Usually, substituents at C-3 (R2) modify the overall pharmacokinetic

properties, whereas those at C-7 (R1) alter the antibacterial

spectrum.

• R1 – the substituents at this position effects β-lactamase

resistance and its activity against Gram –ve and/or Gram +ve bacteria

(its spectrum).

• R2 –these substituents primarily affect the pharmacokinetics: the oral

activity, the extent of metabolism, and the duration of action.

• Electron withdrawing group at this position provide resonance

structure and thus increase stability of the structure.

• Carboxylic acid group –necessary for activity, this functional group

mimics the carboxylic acid group of alanine when binding the enzyme

active site.

[pic]

STEP 5: Key Points (10 minutes)

• The cephalosporins are a class of β-lactam antibiotics originally derived

from the fungus Acremonium, which was previously known as

"Cephalosporium".

• Cephalosporins have broder gram –ve coverage than penicillin yet no one

of the cephalosporins is active against MRSA and enterococci. Basic

structure of cephalosporin is 7-aminocephalosporanic acid.

• Important parameters for the SAR of Cephalosporins which are used to

modify its activity includes beta lactam ring, 2-Carboxyl Group, X-

Substituent,3- Substituent (R3) and 7- substituent (R7).

STEP 6: Evaluation (10 minutes)

• What are Cephalosporins?

• Draw general chemical structure of cephalosporins.

• What is the importance of structure – activity relationship of

cephalosporins?

References.

Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United

States: W.B. Saunders Co.

Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,

India: Prentice Hall of India

Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,

United States: John Willey and Sons.

Nadendla R. R. (2005). Principles of Pharmaceutical Organic Chemistry. New

Delhi, India: MacMillan Publishers

Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:

Prentice Hall Pearson.

Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry (10th Ed.). Calfornia, United

States: Lippincott Williams

Bhassin S.K, Gupta R.(2013). Pharmaceutical organic chemistry (E-book

Kindle edition). New Delhi, India: Elsevier Publishing Service

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