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

Abstract：

: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 1.62Å and angle of C-N-P is 123.6°. Phosphonamidate 1(a-e) showed to be inhibitors of VanX with IC(50) values of 0.39, 0.70, 1.12, 2.82, and 4.13mM, 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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Yang KW,Cheng X,Zhao C,Liu CC,Jia C,Feng L,Xiao JM,Zhou LS,Gao HZ,Yang X,Zhai L

doi

10.1016/j.bmcl.2011.09.020

subject

Has Abstract

pub_date

2011-12-01 00:00:00

pages

7224-7

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)01255-8

journal_volume

21

pub_type

杂志文章

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