SAR of Sulphonamides

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Chapter: Medicinal Chemistry : Antibacterial Sulphonamides

The major features of SAR of sulphonamides include the following:

SAR of Sulphonamides

The major features of SAR of sulphonamides include the following:

·Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity.

·The aminoand sulphonyl-groups on the benzene ring are essential and should be in 1 and 4 position.

·The N-4 amino group could be modified to be prodrugs, which are converted to free amino function in vivo.

·Sulphur atom should be directly linked to the benzene ring.

·Replacement of benzene ring by other ring systems or the introduction of additional substituents on it decreases or abolishes its activity.

·Exchange of the –SO2NH group by –CONH reduces the activity.

·On N-1-substituted sulphonamides, activity varies with the nature of the substituent at the amino group. With substituents imparting electron-rich characters to SO2 group, bacteriostatic activity increases.

·Heterocyclic substituents lead to highly potent derivatives, while sulphonamides, which contain a single benzene ring at N-1 position, are considerably more toxic than heterocyclic ring analogues.

·The free aromatic amino groups should reside para to the sulphonamide group. Its replacement at ortho or meta position results in compounds devoid of antibacterial activity.

·The active form of sulphonamide is the ionized, maximum activity that is observed between the pKa values 6.6–7.4.

·Substitutions in the benzene ring of sulphonamides produced inactive compounds.

·Substitution of free sulphonic acid (–SO3H) group for sulphonamido function destroys the activity, but replacement by a sulphinic acid group (–SO2H) and acetylation of N-4 position retains back the activity.

·m. Sulphonamides bind to the basic centres of arginine, histidine, and lysine sites of proteins. The binding groups are alkyl, alkoxy, and halides. The binding affects the activity of sulphonamides; protein binding appears to modulate the availability of the drug and its half-life.

·The lipid solubility influences the pharmacokinetic and antibacterial activity, and so increases the half-life and antibacterial activity in vitro.

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