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<p>A set of representative simple phosphinamides were synthesised and their physicochemical and metabolic properties were compared with matched pairs of benzamides and sulfonamides. We also synthesised phosphinamide analogues of some marketed drugs and compared the properties of the synthesised analogues with the known compounds. We found that phosphinamides have attractive physicochemical properties for incorporation into drug molecules, being lipophilicity lowering and generally solubility improving. Metabolic stabilities, hydrogen bond donor strengths and Caco-2 permeabilities of phosphinamides were similar to amide and sulfonamide analogues. The experimental polar surface area, surprisingly, showed a smaller difference between secondary and tertiary phosphinamides than for the corresponding benzamides and benzene sulfonamides. Chemical stability, however, is poor in acidic media and even on storage in DMSO solution and constitutes a significant liability for wider use of this functionality in medicinal chemistry.</p><p></p>

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An investigation of phosphinamides as a functional group for medicinal chemistry

  • 期刊论文

  • 发表日期：

    2025年11月7日

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  • Virginie Meurillon,
  • Paul Blanchart,
  • Victoria Ullah,
  • Diana Chan,
  • Matthew Perry

摘要

A set of representative simple phosphinamides were synthesised and their physicochemical and metabolic properties were compared with matched pairs of benzamides and sulfonamides. We also synthesised phosphinamide analogues of some marketed drugs and compared the properties of the synthesised analogues with the known compounds. We found that phosphinamides have attractive physicochemical properties for incorporation into drug molecules, being lipophilicity lowering and generally solubility improving. Metabolic stabilities, hydrogen bond donor strengths and Caco-2 permeabilities of phosphinamides were similar to amide and sulfonamide analogues. The experimental polar surface area, surprisingly, showed a smaller difference between secondary and tertiary phosphinamides than for the corresponding benzamides and benzene sulfonamides. Chemical stability, however, is poor in acidic media and even on storage in DMSO solution and constitutes a significant liability for wider use of this functionality in medicinal chemistry.