BSBT 518Medicinal Chemistry,

Drug Discovery and Development

Presentation 1

Sulphonamides

Presented bySakshi Saxena

IBT VII semASU2013010200124

1. Introduction2. History of Sulphonamides3. Structure-Activity-Relationship4. Sulphonamide analog and its

importance5. Solubility and toxicity6. Mechanism of action7. Resistance to Sulphonamides8. Applications of Sulphonamide9. Side effects of Sulphonamide

IntroductionSulphonamide

is a class of organic compounds that are amides of sulphonic acids, some of which are sulphadrugs and act as powerful inhibitors of

bacterial activity.

Examples are sulphadimidine and sulphadiazine.

•In 1935, it was discovered that a red dye called prontosilhad antibacterial properties in vivo (i.e. when given to laboratory animals).

•But no antibacterial effect was observed in vitro . In other words, prontosil could not kill bacteria grown in the test tube.

•Later it was discovered that prontosil was metabolized by bacteria present in the small intestine of the test animal to give a product called sulphanilamide.

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•It was this compound which was the true antibacterial agent.

•Thus, prontosil was an early example of a prodrug

SAR

1. Para -amino group : This is essential for activity and must be unsubstituted The only exception is when R1 = acyl (i.e. amides).

2. The aromatic ring and the sulphonamide functional group are both required and both must be directly attached to the aromatic ring;3. The aromatic ring must be para -substituted only.4. The sulphonamide nitrogen must be primary or secondary. 5. R2 is the only possible site that can be varied in sulphonamides.

Importance of substitution at R2Sulphonamide analogues

with reduced toxicityThe primary amino group of sulphonamides is acetylated in the body and the resulting amides have reduced solubility which can lead to toxic effects.

Ex : Sulphathiazole

Fatal if it blocks the kidneytubules

Importance of substitution at R2Sulphonamide analogues

with reduced toxicityThe primary amino group of sulphonamides is acetylated in the body and the resulting amides have reduced solubility which can lead to toxic effects.

Ex : Sulphathiazole

Solution

Substitute the thiazole ring in sulphathiazole with a pyrimidine ring to give sulphadiazine

Comparing solubility

In this, NH proton is not very acidic (high p K a ). Therefore, sulphathiazole and its metabolite are mostly un-ionized at blood pH.

Replacing the thiazole ring with a more electron-withdrawing pyrimidin ring increases the acidity of the NH proton by stabilizing the resulting anion.

Hence, sulphadiazine and its metabolite are significantly ionized at blood pH. As a consequence, they are more soluble and less toxic.

Silver sulphadiazine cream is still used topically to prevent infection of burns

Sulphathiazole Sulphadiazine

Mechanism of actionThey act as competitive enzyme inhibitors of dihydropteroate synthetase and block the biosynthesis of tetrahydrofolate in bacterial cells

Sulphonamides are bacteriostatic in nature.

It is an enzyme cofactor for the synthesis of the pyrimidine nucleic acid bases required for DNA synthesis both for bacteria as well as humans.

Sulphonamides act as inhibitors by mimicking p -aminobenzoic acid (PABA)—one of the normal substrates for dihydropteroate synthetase.

Mechanism of action

•Sulphonamides are competitive enzyme inhibitors so inhibition is reversible.

•This is demonstrated by certain organisms, such as staphylococci, pneumococci, and gonococci, which can acquire resistance by synthesizing more PABA.

•The more PABA there is in the cell, the more effectively it can compete with the sulphonamide inhibitor to reach the enzyme’s active site.

Resistance to sulphonamides can also arise by mutations that modify the target enzyme such that it has less affinity for sulphonamides.

RESISTANCE TO SULPHONAMIDE

Application of Sulphonamide as antimalarial drug

The sulphonamide inhibits the incorporation of PABA into

dihydropteroate, while trimethoprim inhibits dihydrofolate reductase.

Cotrimoxazole = Sulphamethoxazole + Trimethoprim

This approach has been described as

sequential blocking .

Other applications

Side Effects

ReferencesPatrick, G. L. (n.d.). Section E Chapter 19 Antibacterial Agents. In An Introduction to Medicinal Chemistry (5th ed.). Oxford University Press.

Aastha pareek , Priyanka rani and D. Kishore. A short review on: sulphonamides . int j pharm bio sci 2013 oct; 4(4): (p) 812 - 820

Joachim K. Seydel . Sulfonamides, Structure-Activity Relationship, and Mode of ActionJournal of Pharmaceutical sciences Volume 57, Issue 9, Pages 1455–1478

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