Bioisosterism sulfonamides

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

Habeeb, A. G., Praveen Rao, P. N., Knaus, E. E. Design and synthesis of celecoxib and rofecoxib analogues as selective cycloox-ygenase-2 (COX-2) inhibitors replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere. 7. Med. Chem. 2001,44(18), 3039-3042. 

Validated hits were mostly carboxylic acids or bioisosteres (tetrazole, sulfonamides)... 

Direct derivatives comprise hydroxamic acids, acyl-cyanamides and acyl-sulfonamides, in which an acidic NH group replaces the acidic OH group. These bioisosteres are mainly of academic interest. Exceptions are the anti-inflammatory hydroxamates bufexamac ibu-... 

Fig. 2.38. Bioisosteric replacement of m-OH of isoproterenol with a sulfonamide group and similar hydrogen-bonding capacity to a possible drug receptor.

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

Initial replacements of the amide functional group with other bioisosteres such as sulfonamide, ester, amine, and retro-amide lost the potency. This exercise confumed the importance of the hydrogen bonding between the carbonyl group (mostly as tautomer 2 ) on quinolinone with the amide carbonyl group. The fruit of this SAR yielded indole 5 (ECso = 9 nM), which was 10-fold more potent than indole 4. 

Acylsulfonamides have important applications as carboxylic add bioisosteres in medidnal chemistry. Thus, it was of great interest to examine sulfonamides as nudeophiles in microwave-heated carbonylations. Starting from the conditions reported for the hydrazidocarbonylations, it was revealed that by simply changing the solvent from THF to 1,4-dioxane, aryl iodides and primary sulfonamides were... 

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