The sulfonamide group as a structural alert: A distorted story?
1Sandwich Laboratories, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. dennis.a.smith@pfizer.com
Current Opinion in Drug Discovery & Development
|January 5, 2008
Summary
Sulfonamide antibacterials, while effective inhibitors of tetrahydropteroic acid synthetase, are often misattributed for hypersensitivity reactions. This review clarifies that the sulfonamide moiety is safe and essential in medicinal chemistry.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Safety
Background:
- The sulfonamide group is prevalent in medicinal chemistry, notably in sulfonamide antibacterials.
- Sulfonamide antibacterials function as inhibitors of tetrahydropteroic acid synthetase.
- These drugs are derivatives of 4-aminobenzenesulfonamide, mimicking 4-aminobenzoic acid.
Purpose of the Study:
- To clarify the origin of hypersensitivity reactions attributed to sulfonamide-containing drugs.
- To differentiate between the effects of the sulfonamide moiety and the 4-amino group.
- To provide scientific evidence supporting the safety and utility of the sulfonamide group in drug design.
Main Methods:
- Literature review of sulfonamide antibacterial mechanisms and toxicity profiles.
- Analysis of historical and current drug labeling and warnings.
- Examination of the chemical structure-activity relationship of sulfonamides.
Main Results:
- Hypersensitivity reactions are primarily linked to the 4-amino (aniline) structure, not the sulfonamide group itself.
- The term 'sulfa allergy' has been historically misapplied to various sulfonamide-containing drugs.
- Scientific evidence supports the sulfonamide group as a safe and crucial component in medicinal chemistry.
Conclusions:
- The sulfonamide moiety is a safe and indispensable pharmacophore in drug development.
- Misattribution of toxicities has led to inaccurate drug warnings.
- Correct understanding of sulfonamide-related adverse effects is crucial for medicinal chemists.
Related Concept Videos
01:23Amines to Sulfonamides: The Hinsberg Test
The Hinsberg test is a method to identify primary, secondary and tertiary amines, named after its pioneer, Oscar Hinsberg. Here, amines are treated with benzenesulfonyl chloride, also known as the Hinsberg reagent, in the presence of an excess of aqueous base, followed by acidification. Based on the nature of the amines, different changes are observed.
Generally, a primary amine reacts with the Hinsberg reagent to produce an N-substituted benzenesulfonamide. The electron-withdrawing sulfonyl...
Generally, a primary amine reacts with the Hinsberg reagent to produce an N-substituted benzenesulfonamide. The electron-withdrawing sulfonyl...
02:17Structure and Nomenclature of Thiols and Sulfides
Thiols and sulfides are sulfur analogs of alcohols and ethers, respectively, where the sulfur atom takes the place of the oxygen atom. Thus, thiols are generally represented as RSH, where R is an alkyl substituent and —SH is the functional group. On the other hand, in sulfides, the central sulfur atom is bonded to two hydrocarbon groups on either side. Depending upon the type of group, sulfides can be either symmetrical or asymmetrical. Both thiols and sulfides display a bent geometry, similar...
02:26Preparation and Reactions of Sulfides
Sulfides are the sulfur analog of ethers, just as thiols are the sulfur analog of alcohol. Like ethers, sulfides also consist of two hydrocarbon groups bonded to the central sulfur atom. Depending upon the type of groups present, sulfides can be symmetrical or asymmetrical. Symmetrical sulfides can be prepared via an SN2 reaction between 2 equivalents of an alkyl halide and one equivalent of sodium sulfide.
01:22Electrophilic Aromatic Substitution: Sulfonation of Benzene
Sulfonation of benzene is a reaction wherein benzene is treated with fuming sulfuric acid at room temperature to produce benzenesulfonic acid. Fuming sulfuric acid is a mixture of sulfur trioxide and concentrated sulfuric acid.
01:19Diazonium Group Substitution: –OH and –H
Nitrous acid, a weak acid, is prepared in situ via the reaction of sodium nitrite with a strong acid under cold conditions. This nitrous acid prepared in situ reacts with primary arylamines to form arenediazonium salts. Such reactions are known as diazotization reactions. As shown in Figure 1, the formation of arenediazonium salts begins with the decomposition of nitrous acid in an acidic solution to give nitrosonium ions.
01:11Aryldiazonium Salts to Azo Dyes: Diazo Coupling
The reaction of weakly electrophilic aryldiazonium (also called arenediazonium) salts with highly activated aromatic compounds leads to the formation of products with an —N=N— link, called an azo linkage. This reaction, presented in Figure 1, is known as diazo coupling and occurs without the loss of the nitrogen atoms of the aryldiazonium salt. Highly activated aromatic compounds such as phenols or arylamines favor the diazo coupling reaction. The coupling generally occurs at the para position.