Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
J Pharm Sci. 2011 Mar;100(3):1001-8. doi: 10.1002/jps.22347. Epub 2010 Oct 18.
Sulfenamide prodrugs of amide and urea functional group containing drugs have recently been proposed as a means of altering the physical and bioproperties of problematic drug molecules containing these two functionalities. Sulfenamides have been shown to revert to the parent drug via reaction with thiols. Explored here is the mechanism for this reaction. The stoichiometry and pH dependency of the in vitro reversion of two model prodrugs of the oxazolidinone, linezolid, and a sulfenamide of phthalimide were studied at 25 °C in the presence of thiols, including cysteine and glutathione, of varying basicity. High-performance/pressure liquid chromatography and liquid chromatography-mass spectrometry results showed the near quantitative reversion of the sulfenamides to the parent drug with simultaneous formation of a mixed disulfide. The pH and the dependency of the reaction on the basicity of the thiol strongly supported the role of the thiolate species in the conversion. The reaction is consistent with an S(N)2 type mechanism seen in the reaction of some thiols with disulfides.
含酰胺和脲基官能团的磺胺前药最近被提议作为一种改变含有这两种官能团的有问题药物分子的物理和生物特性的方法。已经表明磺胺可以通过与巯基反应恢复为母体药物。本文探讨了这种反应的机制。在 25°C 下，在不同碱性的巯基（包括半胱氨酸和谷胱甘肽）存在下，研究了两种恶唑烷酮（利奈唑胺）和邻苯二甲酰亚胺磺胺前药的体外还原的化学计量和 pH 依赖性。高效/压力液相色谱和液相色谱-质谱结果表明，磺胺几乎定量地转化为母体药物，同时形成混合二硫键。反应的 pH 值和对巯基碱性的依赖性强烈支持了硫醇化物在转化中的作用。该反应与一些巯醇与二硫化物反应中观察到的 S(N)2 型机制一致。
