NTA Level 5 • Semester 1 • PST05106

Structure – Activity Relationship of Aspirin

Pharmaceutical Organic Chemistry • Source Session/Topic 30

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Session 30: Structure – Activity Relationship of Aspirin.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

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

• Define Aspirin

• Explain Chemical structure of aspirin

• Explain the structure – activity relationship of aspirin

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 Aspirin (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What is Aspirin? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the table below |

• Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) effective in

treating fever, pain, and inflammation in the body.

• It also prevents blood clots (i.e., is antithrombotic). As a group,

NSAIDs are non-narcotic relievers of mild to moderate pain of many

causes, including

o Headaches,

o Injury,

o Menstrual cramps,

o Arthritis, and other musculoskeletal conditions

• Other members of this class include

o ibuprofen (Motrin),

o indomethacin (Indocin),

o nabumetone (Relafen) and several others.

• They all work by reducing the levels of prostaglandins, chemicals that

are released when there is inflammation and that cause pain and fever.

• NSAIDs block the enzyme that makes prostaglandins (cyclooxygenase),

resulting in lower concentrations of prostaglandins.

• As a consequence, inflammation, pain, and fever are reduced.

• Inhibition of prostaglandins also reduces the function of platelets

and the ability of blood to clot.

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

• Acetylsalicylic acid –or, as it is more commonly known, aspirin –has a

simple chemical structure.

• It consists of a small number of carbons, hydrogen and oxygen atoms that

form the chemical bonding patterns shown below.

• Aspirin Acetylsalicylic acid C9H8O4

[pic]

• One of the best-known aromatic acetates is acetylsalicylic acid, or

aspirin, which is prepared by the esterification of the phenolic

hydroxyl group of salicylic acid.

[pic]

• Aspirin possesses a number of properties that make it the most often

recommended drug which are;

o analgesia, leading to pain relief

o anti-inflammatory effect, providing some relief from the swelling

associated with arthritis and minor injuries.

o antipyretic effect, which means it reduces fever.

Synthesis

• The key compound in the synthesis of aspirin, salicylic acid, is

prepared from phenol by Kolbe synthesis (also known as the Kolbe-

Schmitt reaction) whereby sodium phenoxide is heated with CO2 under

pressure and the reaction mixture is subsequently acidified to yield

salicylic acid.

[pic]

STEP 4: Structure – Activity relationship of Aspirin (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 aspirin? |

| |

|ALLOW students to discuss for 15 minutes. |

| |

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

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Despite the vast effort that has been expended in the search to find a

“better” aspirin—that is, one possessing fewer GI side effects, but a

greater potency and a longer duration of action yet is inexpensive and an

antipyretic, analgetic, and anti-inflammatory agent that is overall

superior to aspirin—none has yet to be discovered.

The following structure–activity relationships have been established:

[pic]

• Possesses a free carboxylic acid (COOH) for an ionic interaction with

the positively charged arginine residue at the active site of the

cyclooxygenases (i.e., Arg-120 in COX-1 or Arg-106 in COX-2 isozymes).

• This acidic moiety is further linked to an aromatic (or

heteroaromatic) ring for binding to either the Δ5-double-bond or Δ8-

double-bond binding regions.

• The active moiety appears to the salicylate anion.

• The side effects of aspirin, particularly the GI effects, appear to be

associated with the carboxylic acid function.

• Reducing the acidity of this group (e.g., converting to an amide,

salicylamide) maintains the analgesic actions of salicylic acid

derivatives but eliminates the anti-inflammatory properties.

• Substitution on either the carboxyl or phenolic hydroxyl groups may

affect potency and toxicity.

• Benzoic acid itself has only weak anti-inflammatory activity.

• Placing the phenolic hydroxyl group meta or para to the carboxyl group

abolishes this activity.

• Substitution of halogen atoms on the aromatic ring enhances potency

and toxicity.

• Substitution of aromatic rings at the 5-position of salicylic acid

increases anti-inflammatory activity (e.g., diflunisal).

STEP 5: Key Points (10 minutes).

• Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) effective in

treating fever, pain, and inflammation in the body.

• Aspirin possesses a free carboxylic acid (COOH) for an ionic

interaction with the positively charged arginine residue at the active

site of the cyclooxygenases.

• Modification of carboxylic acid function group of aspirin may help in

reducing its GI toxicity.

STEP 6: Evaluation (10 minutes).

• What is Aspirin?

• Draw chemical structure of aspirin.

• What is the importance of structure – activity relationship of

aspirin?

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.

Rama Rao Nadendla (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 Services

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