Prodrug forms for the sulfonamide group. III. Chemical and enzymatic hydrolysis of various N-sulfonyl imidates—a novel prodrug form for a sulfonamide group or an ester function

Abstract

The kinetics and mechanism of degradation of a series of N-sulfonyl imidate esters derived from various model sulfonamides as well as from carbonic anhydrase inhibitors were examined in aqueous solution and in human plasma solutions. The hydrolysis of the compounds was subject to specific acid and base catalysis as well as enzymatic catalysis by plasma enzymes. At pH 4–8 or in the presence of plasma all the compounds derived from alcohols and amino alcohols were converted quantitatively to the parent sulfonamide and the corresponding carboxylic acid or carbonate ester. Sulfonyl imidate esters derived from phenols hydrolyzed to yield N-acyl sulfonamide and the parent phenol. The influence of various structural factors on the reactivity of the sulfonyl imidate esters was examined. The results suggest that the N-sulfonyl imidate esters are potentially useful prodrug forms containing a primary sulfonamide group as well as for carboxylic acid esters derived from aliphatic alcohols.