Synthesis and activity study of phosphonamidate dipeptides as potential inhibitors of VanX

In an effort to develop inhibitors of VanX, the phosphonamidate analogs of d-Ala-d-Ala dipeptides, N-[(1-aminoethyl) hydroxyphosphinyl]-glycine (1a), -alanine (1b), -valine (1c), -leucine (1d) and -phenylalanine (1e) were synthesized, characterized and evaluated using recombinant VanX. The crystal structure of the intermediate 6d was obtained (Deposition number: CCDC 839134), and structural analysis revealed that it is orthorhombic with a space group P2(1)2(1)2(1), the bond length of P–N is 1.62 Å and angle of C–N–P is 123.6°. Phosphonamidate 1(a–e) showed to be inhibitors of VanX with IC50 values of 0.39, 0.70, 1.12, 2.82, and 4.13 mM, respectively, which revealed that the inhibition activities of the phosphonamidates were dependent on the size of R-substituent of them, with the best inhibitor 1a having the smallest substituent. Also, 1a showed antibacterial activity against Staphylococcus aureus (ATCC 25923) with a MIC value of 0.25 μg/ml.

Graphical abstractFive phosphonamidate analogs (1a–e) of d-Ala-d-Ala dipeptides displayed inhibitory activity against VanX with IC50 values of 0.39, 0.70, 1.12, 2.82 and 4.13 mM, also 1a showed an antibacterial activity against Staphylococcus aureus (ATCC 25923) with a MIC value of 0.25 μg/ml.Figure optionsDownload full-size imageDownload as PowerPoint slide