Sulfonamides physicochemical properties

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

The sulfonamide can have superior bioavailability and physicochemical properties that are manifested in greater in vivo efficacy in the anti-inflammatory models. Celecoxib has incorporated the sulfonamideas a balance of selectivity and in vivo efficacy. The JTE-522 compound (73)introduced a flu-... 

A large proportion of drug substances, whether neutral molecules, free adds, free bases or salts, are capable of exhibiting polymorphism or pseudopolymorphism (hydrate or solvate formation). It has been reported that 70% of barbiturates, 60% of sulfonamides and 23% of steroids exhibit polymorphism." Polymorphism often influences a range of physicochemical properties such as solubility, dissolution rate, stability and powder properties as well as bioavailability. Usually, it is possible to determine the most stable polymorph and discover recrystallization solvents that uniquely produce this form and improve the physicochemical and physicome-chanical properties and chemical stability of the drug. 

Mengelers MJ, Hougee PE, Janssen LH, Van Miert AS. Structure-activity relationships between antibacterial activities and physicochemical properties of sulfonamides. J Vet Pharmacol Ther 1997 Aug 20(4) 276-283. 

B. Sulfonamides Including Benzylpyrimidine Sulfonamides L Physicochemical and Pharmacologic Properties... 

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