Sulfoximines from a Medicinal Chemist's Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery

Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space

“…The hydrophilicity increased in the following series: 20 < 23 < 21 < 22 (the Log D 7.4 values were 1.99±0.02, 0.25±0.02, −1.35±0.12, and −1.90±0.03, respectively). It is interesting to note that imidosulfuric diamide 20 (Log D 7.4 =1.99±0.02) was considerably more hydrophobic than the corresponding sulfuric diamide 23 (Log D 7.4 =0.25±0.02); this is contrary to the case of sulfoximines and sulfones, which demonstrate similar hydrophilicity . All four compounds 20 – 23 showed high mouse microsomal stability; it should be noted that, although compound 23 showed a slight decrease in its concentration in all experiments, the corresponding imidosulfuric diamide 20 appeared to be fairly stable.…”

“…Organosulfur(VI) derivatives with S=N bonds (e.g., sulfoximines or sulfonimidamides) have attracted much interest recently . It was shown that these compounds can be considered as bioisosteres of sulfones and sulfonamides, respectively (Figure ), with improved physicochemical characteristics and pharmacokinetic profile . It is not surprising, therefore, that significant synthetic efforts have been put into the development of convenient methods for their preparation …”

One‐Pot, Three‐Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine Reagent N‐Sulfinyltritylamine, TrNSO

“…[1] Like their congeners,t hey are chemically and metabolically stable, [2] but in addition, the substitution of an oxygen atom for an itrogen leads to astereogenic sulfur center,presents further opportunities for directed hydrogen bonding,a nd provides an additional site for functionalization. [1] Like their congeners,t hey are chemically and metabolically stable, [2] but in addition, the substitution of an oxygen atom for an itrogen leads to astereogenic sulfur center,presents further opportunities for directed hydrogen bonding,a nd provides an additional site for functionalization.…”

Increasing Complexity: A Practical Synthetic Approach to Three‐Dimensional, Cyclic Sulfoximines and First Insights into Their in Vitro Properties

“…In contrast to sulfones 1 , sulfoximines 2 offer an additional point for substitution, namely the mildly basic nitrogen atom, which can also be utilized for the construction of cyclic sulfoximines 3 (Figure ), for example by connecting the substituents R 2 and R 3 . Recent reports have suggested that the introduction of NH‐sulfoximines 2 (R 3 =H) into certain lead structures can result in reduced Caco2 permeability and increased efflux . In principle, masking of the hydrogen‐bond donor function of the sulfoximine NH group ( 2 , R 3 =H) by N‐alkylation ( 2 , R 3 =alkyl) should be a means to improve membrane permeability, but there are only scattered reports.…”