NTA Level 5 • Semester 1 • PST05106

Structure – Activity Relationship of Paracetamol

Pharmaceutical Organic Chemistry • Source Session/Topic 31

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Session 31: Structure – Activity Relationship of Paracetamol.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

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

• Define Paracetamol

• Explain Chemical structure of paracetamol

• Explain the structure – activity relationship of paracetamol

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 Paracetamol (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What is paracetamol? |

| |

|ALLOW few students to respond. |

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|WRITE their responses on the flip chart/ board. |

| |

|CLARIFY and SUMMARISE by using the table below |

• Paracetamol also known as acetaminophen is an analgesic antipyretic

derivative of acetanilide.

• Acetaminophen has weak anti-inflammatory properties and is used as a

common analgesic, but may cause liver, blood cell, and kidney damage.

• Acetaminophen is a p-aminophenol derivative with analgesic and

antipyretic activities.

• Although the exact mechanism through which acetaminophen exert its

effects has yet to be fully determined, acetaminophen may inhibit the

nitric oxide (NO) pathway mediated by a variety of neurotransmitter

receptors including N-methyl-D-aspartate (NMDA) and substance P,

resulting in elevation of the pain threshold.

• The antipyretic activity may result from inhibition of prostaglandin

synthesis and release in the central nervous system (CNS) and

prostaglandin-mediated effects on the heat-regulating center in the

anterior hypothalamus.

• Acetaminophen is a widely used nonprescription analgesic and antipyretic

medication for mild-to-moderate pain and fever.

• Harmless at low doses, acetaminophen has direct hepatotoxic potential

when taken as an overdose and can cause acute liver injury and death from

acute liver failure.

• Even in therapeutic doses, acetaminophen can cause transient serum

aminotransferase elevations.

Summary

• Paracetamol (acetaminophen) is a pain reliever and a fever reducer.

• Paracetamol is used to treat many conditions such as headache, muscle

aches, arthritis, backache, toothaches, colds, and fevers. It relieves

pain in mild arthritis but has no effect on the underlying

inflammation and swelling of the joint.

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

• The acetaminophen has the IUPAC name N-(4-hydroxyphenyl) acetamide and

its chemical formula us C8H9NO2 and its extended formula is

HOC6H4NHCOCH3.

• Its molar mass is 151.165 g mol-1.

• The molecule is formed by an aromatic phenyl ring, which has two

substituents in position -para (1,4).

• The first substituent is an amide group (acetamide) and the second is

a hydroxy group (-OH).

• The molecule is planar with 7 carbon atoms with sp2 hybridization.

• Its chemical structure can be written as below, in the common

representations used for organic molecules.

[pic]

STEP 4: Structure – Activity relationship of Paracetamol (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 paracetamol? |

| |

|ALLOW students to discuss for 15 minutes. |

| |

|ALLOW few groups to present for 5 minutes and the rest to add points |

|not mentioned. |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Paracetamol consists of a benzene ring core, substituted by one

hydroxyl group and the nitrogen atom of an amide group in the para

(1,4) pattern.

• The amide group is acetamide (ethanamide).

• It is an extensively conjugated system, as the lone pair on the

hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p

orbital on the carbonyl carbon, and the lone pair on the carbonyl

oxygen is all conjugated.

• The presence of two activating groups also makes the benzene ring

highly reactive toward electrophilic aromatic substitution.

• As the substituents are ortho,para-directing and para with respect to

each other, all positions on the ring are more or less equally

activated.

• The conjugation also greatly reduces the basicity of the oxygens and

the nitrogen, while making the hydroxyl acidic through delocalisation

of charge developed on the phenoxide anion.

• Structure and reactivity of acetaminophen accounts for its chemical

properties

• Based on the comparative toxicity of acetanilide and acetaminophen,

aminophenols are less toxic than the corresponding aniline derivatives,

although p-aminophenol itself is too toxic for therapeutic purposes.

• Etherification of the phenolic function with methyl or propyl groups

produces derivatives with greater side effects than with ethyl groups.

Substituent

• The nitrogen atoms that reduce basicity reduce activity unless that

substituent is metabolically labile (e.g., acetyl).

• Amides derived from aromatic acids (e.g., N-phenylbenzamide) are less

active or inactive.

• As indicated, both acetanilide and phenacetin are metabolized to

acetaminophen. Additionally, both undergo hydrolysis to yield Aniline

derivatives that produce directly, or through their conversion to

hydroxylamine derivatives, significant methemoglobinemia and hemolytic

anemia, which resulted in their removal from the U.S. market.

STEP 5: Key Points (10 minutes)

• Paracetamol also known as acetaminophen is an analgesic antipyretic

derivative of acetanilide

• The SAR of paracetamol may help in reducing its hepatotoxicity.

STEP 6: Evaluation (10 minutes)

• What is Paracetamol?

• Draw the Chemical structure of paracetamol.

• What is the importance of structure – activity relationship of

paracetamol?

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.). California, United

States: Lippincott Williams

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

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

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