NTA Level 5 • Semester 1 • PST05106

Structure – Activity Relationship of Sulphonamides

Pharmaceutical Organic Chemistry • Source Session/Topic 29

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Session 29: Structure – Activity Relationship of Sulphonamides.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

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

• Define Sulphonamides

• Explain chemical structure of sulphonamides

• Explain the structure – activity relationship of sulphonamides

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 Sulphonamides (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Sulphonamides? |

| |

|ALLOW few students to respond. |

| |

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

| |

|CLARIFY and SUMMARISE by using the table below |

Sulphonamides are antibacterial agents which acts against cell metabolism

(antimetabolites).

Sulfonamides:

• Once known as ‘wonder drug’.

• Once mainstays of antimicrobial chemotherapy.

• The relative cheapness of the sulphonamides is one of their most

attractive features and accounts for much of their persistence in the

market.

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

• Sulphonamides are composed of a sulphur atom that has two sets of

double bonds to two oxygen atoms, a carbon-based side group, and a

nitrogen atom bonded to the sulphur itself.

• In organic chemistry, an amide contains a carbonyl group bonded to a

nitrogen atom.

• Sulphonamides are similar, but the carbonyl group is replaced with

sulfone sulphur with two oxygen atoms).

• That's why the term 'amide' appears in the name.

[pic]

General structure of amides and

sulphonamides.

• The 'R' groups in the figure simply represent any generic carbon-based

side chain and could be virtually anything.

• For example, R could be a methyl group, a benzene ring, an alkane

ring, or some other group.

• If the nitrogen atom contains two hydrogens, the sulphonamide is

classified primary, if there is one hydrogen it's secondary, and if no

hydrogens are present on the nitrogen, it's a tertiary sulphonamide

[pic]

Structures of primary, secondary, and tertiary

sulphonamides.

Important Sulfonamide Derivatives

• Sulfamethoxazole

• Sulfamethoxazole is another sulfonamide with antibacterial activity

and is commonly used in the treatment of urinary tract infections and

bronchitis.

• Sulfamethoxazole looks very similar to sulfanilamide in terms of its

structure but contains an extra ring system called an oxazole.

[pic]

STEP 4: Structure – Activity Relationship of Sulphonamides (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 sulphonamides? |

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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 |

The synthesis of a large number of sulphonamide analogues led to the

following conclusions

[pic]

Sulfonamides analogues

• The para -amino group is essential for activity and must be unsubstituted

(i.e. R1=H). The only exception is when R1=acyl (i.e. amides).

• The amides themselves are inactive but can be metabolized in the body to

regenerate the active compound.

• Thus, amides can be used as sulfonamide prodrugs.

• Incorporation of other groups (halogen, alkyl, etc.) destroys the

activity.

[pic]

Metabolism of acyl group to regenerate active

compound

• The aromatic ring and the sulphonamide functional group are both

required.

• Total loss of antibacterial activity occurs if sulphonamide group is

replaced by other acidic groups (sulfonic, phosphoric etc.)

• The aromatic ring must be para -substituted only.

• Extra substitution eliminates activity for steric reasons.

• The sulfonamide nitrogen must be primary (sulfanilamide) or secondary

(acidic proton is essential for antibacterial activity).

• R2 is the only possible site that can be varied in sulfonamides.

Sulphonamide analogues

• R2 can be varied by incorporating a large range of heterocyclic or

aromatic structures, which affects the extent to which the drug binds to

plasma protein.

• This in turn controls the blood levels of the drug such that it can be

short acting or long acting.

• Thus, a drug which binds strongly to plasma protein will be slowly

released into the blood circulation and will be longer lasting.

• R2 affects pharmacokinetic properties but not the pharmacodynamics

properties.

Sulfonamide analogues with reduced toxicity

• Changing the nature of the group R2 has also helped to reduce the

toxicity of some sulfonamides.

• The primary amino groups of sulfonamides are acetylated in the body and

the resulting amides have reduced solubility which can lead to toxic

effects.

• For example, the metabolite formed from sulfathiazole is poorly soluble

and can prove fatal if it blocks the kidney tubules

[pic]

Insoluble

• It was discovered that the solubility problem could be overcome by

replacing the thiazole ring in sulfathiazole with a pyrimidine ring to

give sulfadiazine.

[pic]

• Its metabolites will also be water soluble

• The reason for the improved solubility lies in the acidity of the

sulphonamide NH proton.

• In sulfathiazole, this proton is not very acidic.

• Therefore, sulfathiazole and its metabolite are mostly un-ionized at

blood pH.

• Replacing the thiazole ring with amore electron withdrawing pyrimidine

ring increases the acidity of the NH proton by stabilizing the resulting

anion.

• Therefore, sulfadiazine and its metabolite are significantly ionized at

blood pH.

• As a consequence, they are more soluble and less toxic.

Treatment of intestinal infections

• Sulphonamides are useful against intestinal infections

• Prodrugs are used for this purpose

• For example, succinyl sulfathiazole is a prodrug of sulfathiazole

[pic]

• The succinyl moiety contains an acidic group which means that the prodrug

is ionized in the slightly alkaline conditions of the intestine.

• As a result, it is not absorbed into the blood stream and is retained in

the intestine.

• Slow enzymatic hydrolysis of the succinyl group then releases the active

sulfathiazole where it is needed.

[pic]

• Benzoyl substitution on the aniline nitrogen has also given useful

prodrugs, which are poorly absorbed through the gut wall since they

are too hydrophobic

STEP 5: Key Points (10 minutes).

• Sulphonamides are composed of a sulphur atom that has two sets of double

bonds to two oxygen atoms, a carbon-based side group, and a nitrogen atom

bonded to the sulphur itself.

• Modification at R2 group may alter the duration of action and toxicity of

sulfonamides.

STEP 6: Evaluation (10 minutes).

• What are Sulphonamides?

• Draw general chemical structure of sulphonamides

• What is the importance of the structure – activity relationship of

sulphonamides?

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.). California, 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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