Synthesis and evaluation of phosphonated N-heteroarylcarboxamides as DOXP-reductoisomerase (DXR) inhibitors

被引：22

作者：

Bodin, Taryn ^{[4
]}

Conibear, Anne C. ^{[1
]}

Blatch, Gregory L. ^{[2
,3
,4
]}

Lobb, Kevin A. ^{[1
,4
]}

Kaye, Perry T. ^{[1
,4
]}

机构：

[1] Rhodes Univ, Dept Chem, ZA-6140 Grahamstown, South Africa

[2] Rhodes Univ, Biomed Biotechnol Res Unit, ZA-6140 Grahamstown, South Africa

[3] Rhodes Univ, Dept Biochem, ZA-6140 Grahamstown, South Africa

[4] Rhodes Univ, Ctr Chem & Biomed Res, ZA-6140 Grahamstown, South Africa

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 03期

基金：

英国医学研究理事会;

关键词：

Anti-malarial; Phosphonates; DOXP-reductoisomerase; Enzyme inhibitors; In silico docking; Saturation Transfer Difference NMR; 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE; SUBSTITUTED FOSMIDOMYCIN ANALOGS; ESTER PRODRUGS; ISOPRENOID BIOSYNTHESIS; PLASMODIUM-FALCIPARUM; NONMEVALONATE PATHWAY; ANTIMALARIAL; BINDING; FR900098; COMPLEX;

D O I：

10.1016/j.bmc.2010.11.062

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The diethyl esters and disodium salts of a range of heteroarylcarbamoylphosphonic acids have been prepared and evaluated as analogues of the highly active DOXP-reductoisomerase (DXR) inhibitor, fosmidomycin. Computer-simulated docking studies, Saturation Transfer Difference (STD) NMR analysis and enzyme inhibition assays have been used to explore enzyme-binding and -inhibition potential, while in silico analysis of the DXR active site has highlighted the importance of including a well-parameterised metal co-factor in docking studies and has revealed the availability of an additional binding pocket to guide future drug design. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：1321 / 1327

页数：7

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