Sulfoximines as Secondary Sulfonamide Isosteres: Paradoxical Impact on Solubility and Plasma Protein Binding.

We report paradoxical findings in properties when secondary sulfonamides are replaced with isosteric secondary sulfoximines. Despite the reduction in polar surface area and the elimination of a hydrogen bond acceptor and a hydrogen bond donor in the RS(O)2NHR to RS(O)(Me) = NR transformation, the resulting sulfoximines generally had increased aqueous solubility and decreased albumin binding, with experimental logP/D values substantially lower than predicted. Despite these characteristics of increased hydrophilicity of the sulfoximine motif, permeability and metabolic stability were similar to those of the corresponding sulfonamide. These studies were enabled by parallel medicinal chemistry via library synthesis facilitated by the use of a palladium precatalyst. We further demonstrate that in comparing molecules over a range of albumin binding, calculating the pseudoaffinity constant (log KHSA) is superior for data interpretation than the more frequently used fraction unbound. The paradoxical findings presented here are indicative of secondary sulfoximines being both more hydrophilic and more lipophilic than their corresponding sulfonamides.