Sulfilimines from a Medicinal Chemist’s Perspective: Physicochemical and in Vitro Parameters Relevant for Drug Discovery

While sulfoximines are nowadays a well established functional
group
for medicinal chemistry, the properties of sulfilimines are significantly
less well studied, and no sulfilimine has progressed to the clinic
to date. In this account, the physicochemical and in vitro properties
of sulfilimines are reported and compared to those of sulfoximines
and other more traditional functional groups. Furthermore, the impact
on the physicochemical and in vitro properties of real drug scaffolds
is studied in two series of sulfilimine-containing analogs of imatinib
and hNE inhibitors. We show that sulfilimines can be chemically and
configurationally stable under physiologically relevant conditions
and that they are basic and highly polar and thus are often beneficial
for solubility and metabolic stability, although at the cost of reduced
permeability. We conclude that S-cyclopropyl,S-(hetero)aryl and S,S-di(hetero)aryl sulfilimines are so far neglected but potentially
valuable S(IV) based pharmacophores that deserve to be considered
as part of the medicinal chemistry toolbox.