title: 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.
authors: Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, PR China. kwyang@nwu.edu.cn
authors: Ke-Wu
authors: KW
authors: Yang
authors: Xu
authors: X
authors: Cheng
authors: Chuan
authors: C
authors: Zhao
authors: Cheng-Cheng
authors: CC
authors: Liu
authors: Chao
authors: C
authors: Jia
authors: Lei
authors: L
authors: Feng
authors: Jian-Min
authors: JM
authors: Xiao
authors: Li-Sheng
authors: LS
authors: Zhou
authors: Hui-Zhou
authors: HZ
authors: Gao
authors: Xia
authors: X
authors: Yang
authors: Le
authors: L
authors: Zhai
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C091956:VanX dipeptidase