Synthesis and Physiochemical Characterization of Sulfenamide Prodrugs of Antimicrobial Oxazolidinones

Abstract

The synthesis, physicochemical characterization and evaluation of sulfenamide derivatives of antimicrobial oxazolidinones as prodrugs are described in this dissertation. Synthesis of sulfenamide derivatives described in this work involves the use of thiophthalimide intermediates. These thiophthalimide intermediates allow for a clean one step reaction, which requires less purification steps resulting in higher yields of sulfenamide products compared to a previously described synthetic route that incorporated the use of unstable sulfuryl chloride intermediates. The sulfenamide prodrugs undergo chemical conversion through the hydrolytic cleavage of the N-S bond during aqueous stability studies to release the parent drug molecule. However, insufficient aqueous stability characteristics may pose potential problems for future development of sulfenamide prodrugs as ready to use liquid formulations. The stability of the sulfenamide prodrugs was studied in the presence of small molecule thiols with varying thiol pKa. These studies showed that the thiolate ion was the species responsible for the nucleophilic attack on the sulfur atom of the N-S bond, leading to the cleavage of the bond to release the parent molecule and a mixed disulfide. Reactions of the sulfenamide prodrugs with thiol containing proteins such as human serum albumin and PRL-1 also resulted in the nucleophilic cleavage of the sulfenamide bond to release the parent molecule. The reactions of the sulfenamide prodrugs with small molecule thiols and thiol containing proteins led to the conclusion that in vivo conversion will occur via the nucleophilic attack of thiolate species. Attempts to study the permeability of the sulfenamide derivatives were hindered by the rapid conversion of the sulfenamide prodrugs to the parent molecule in the transport study setup. This rapid conversion is believed to be caused by the presence of thiol containing proteins on the surface of the Caco-2 cell monolayer and also within the cells. However, analysis of the initial permeability data shows that the sulfenamide prodrugs are contributing to the slight improvement of the permeability of the parent molecule.