Sulfonimidamides as Sulfonamides Bioisosteres: Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ‐Secretase Inhibitors

Abstract

Although not endogenous in nature, the sulfonamide functionality is widely found in organic molecules with biological activity. A search of Thomson Reuters Integrity reveals that the sulfonamide motif appears in 111 approved drugs or agents in clinical trials, [1] and the total number of organic molecules containing this functional group is enormous. In contrast, the sulfonamide isostere [2] in which one of the sulfonamide oxygen atoms have been replaced by a nitrogen atom, thus creating a sulfonimidamide has received little attention in the literature. The first reports on sulfonimidamides were published in the early 1960s, [3] however, it was only during the last few years that the research groups of Malacria [4] and Dodd [5] explored the use of sulfonimidamides as reagents in organic synthesis, while Bolm et al. explored sulfonimidamides as chiral organocatalysts [6a] and as ligands for transition metal-catalyzed asymmetric synthesis.[6b]

Crystal structure of tert-butyl (phenylsulfinyl)carbamate, C11H15NO3S

“…Sulfonimidamide is an isostere of sulphonamide, which is formed by replacing one of the O-atoms by nitrogen of sulfonamide. The title compound can be considered as a potential pecursor for the preparation of sulfonimidamids [9][10][11][12]. However crystal structures of sulfinylcarbamate derivatives are rare.…”

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375

“…A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma has recently been stopped early because of safety issues in the tasisulam arm. Although it was considered to be unlikely that tasisulam was superior to prior chemotherapies, the importance of pharmacokinetic monitoring of compounds with complex dosing was underscored [43]. …”

“…1). For example, Sehgelmeble et al [43] found significant potencies when profiling sulfonimidamide-based analogs of sulfonamidic γ-secretase inhibitors. Furthermore, N-acylated sulfonimidamides were shown to have bioisosteric properties to carboxylic acid [44,45,46,47,48,49].…”

Palladium‐Catalyzed Carbonylation of Aryl Iodides with Sulfinamides

“…[13,14] Sulfonimidamide derivatives were recently evaluated as sulfonamide bioisosteres in γ-secretase inhibitors [11,15] and showed increased solubility, decreased lipophilicity and decreased plasma protein binding in relation to their sulfonamide-containing analogues. [11] Moreover, cyclic sulfonimidamides have been identified as potential carboxylic acid bioisosteres, on the basis of promising physicochemical properties. [16] In line with this, our group recently found complementary results for linear acyl-substituted sulfonimidamides of types III and IV.…”

“…[1,5] Moreover, this functionality serves as a precursor in the preparation of sulfonimidamides (II) [6][7][8][9][10][11][12] and acyl-sulfonimidamides (III and IV). [13,14] Sulfonimidamide derivatives were recently evaluated as sulfonamide bioisosteres in γ-secretase inhibitors [11,15] and showed increased solubility, decreased lipophilicity and decreased plasma protein binding in relation to their sulfonamide-containing analogues. [11] Moreover, cyclic sulfonimidamides have been identified as potential carboxylic acid bioisosteres, on the basis of promising physicochemical properties.…”