Studying Lipophilicity Trends of Phosphorus Compounds by ³¹P-NMR Spectroscopy: A Powerful Tool for the Design of P-Containing Drugs.

ID: ALA5131543

Journal: J Med Chem

Title: Studying Lipophilicity Trends of Phosphorus Compounds by ³¹P-NMR Spectroscopy: A Powerful Tool for the Design of P-Containing Drugs.

Authors: Columbus I, Ghindes-Azaria L, Chen R, Yehezkel L, Redy-Keisar O, Fridkin G, Amir D, Marciano D, Drug E, Gershonov E, Klausner Z, Saphier S, Elias S, Pevzner A, Eichen Y, Parvari G, Smolkin B, Zafrani Y.

Abstract: Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on ³¹P-NMR spectroscopy. The log P values measured ranged between -3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pK_HB) measurements of selected compounds. Clear signal separation in ³¹P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to -250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and ³¹P-NMR analysis.

CiteXplore: 35678759

DOI: 10.1021/acs.jmedchem.2c00658

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