Conroy C W, Schwam H, Maren T H
Drug Metab Dispos. 1984 Sep-Oct;12(5):614-8.
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.
在模拟生理条件下，已测定了还原型谷胱甘肽和L-半胱氨酸与一系列5-取代的1,3,4-噻二唑-和1,3,4-噻二唑啉-2-磺酰胺、稠环1,3,4-噻二唑-2-磺酰胺以及取代苯磺酰胺的非酶促缀合反应速率。在pH 7.5条件下，5-取代的1,3,4-噻二唑-和1,3,4-噻二唑啉-2-磺酰胺（甲醋唑胺衍生物）两个系列内的缀合反应活性符合布朗斯特关系，缀合速率随着磺酰胺pK值降低而增加。发现反应速率从X（pKa = 7.7）的k = 0.07×10⁻³ min⁻¹变化到IX（pKa = 7.05）的k = 275×10⁻³ min⁻¹。所有取代苯磺酰胺以及几种pKa值高于9的1,3,4-噻二唑-2-磺酰胺对缀合反应无活性。这些数据大概解释了许多此类化合物在体内的归宿，例如乙酰唑胺（I）原样排泄而甲醋唑胺（XI）和乙氧唑胺（XVII）部分代谢的事实。
