Sulfilimines\nfrom a Medicinal Chemist’s Perspective:\nPhysicochemical and in Vitro Parameters Relevant for Drug Discovery

While sulfoximines are nowadays a well established functional\ngroup\nfor medicinal chemistry, the properties of sulfilimines are significantly\nless well studied, and no sulfilimine has progressed to the clinic\nto date. In this account, the physicochemical and in vitro properties\nof sulfilimines are reported and compared to those of sulfoximines\nand other more traditional functional groups. Furthermore, the impact\non the physicochemical and in vitro properties of real drug scaffolds\nis studied in two series of sulfilimine-containing analogs of imatinib\nand hNE inhibitors. We show that sulfilimines can be chemically and\nconfigurationally stable under physiologically relevant conditions\nand that they are basic and highly polar and thus are often beneficial\nfor solubility and metabolic stability, although at the cost of reduced\npermeability. We conclude that <i>S</i>-cyclopropyl,<i>S</i>-(hetero)aryl and <i>S</i>,<i>S</i>-di(hetero)aryl sulfilimines are so far neglected but potentially\nvaluable S(IV) based pharmacophores that deserve to be considered\nas part of the medicinal chemistry toolbox.