The nonenzymatic displacement of the sulfamoyl group from different classes of aromatic compounds by glutathione and cysteine
Conroy, C.W.; Schwam, H.; Maren, T.H.
Drug Metabolism and Disposition the Biological Fate of Chemicals 12(5): 614-618
1984
ISSN/ISBN: 0090-9556 PMID: 6149913 Document Number: 228237
The rates of reaction for the nonenzymatic conjugation of reduced glutathione and L-cysteine to a series of 5-substituted 1,3,4-thiadiazole- and 1,3,4-thiadiazoline-2-sulfonamides, ring-fused 1,3,4-thiadiazole-2-sulfonamides, and substituted benzenesulfonamides have been measured under simulated physiological conditions. The reactivities toward conjugation at pH 7.5 within two series of 5-substituted 1,3,4-thiadiazole- and 1,3,4-thiadiazoline-2-sulfonamides (methazolamide derivatives) conformed to the Brønsted relationship, the rate of conjugation increasing as sulfonamide pK, decreased. Reaction rate was found to vary from k = 0.07 X 10(-3) min-1 for X (pKa = 7.7) to k = 275 X 10(-3) min-1 for IX (pKa = 7.05). All substituted benzenesulfonamides and several 1,3,4-thiadiazole-2-sulfonamides with pKa values above 9 were unreactive toward conjugation. The data presumably explain the fate of many of these compounds in vivo, for example the fact that acetazolamide (I) is excreted unchanged while methazolamide (XI) and ethoxolamide (XVII) are partially metabolized.