Towards new antimalarial drugs: Synthesis of non-hydrolyzable phosphate mimics as feed for a predictive QSAR study on 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors
Towards new antimalarial drugs: Synthesis of non-hydrolyzable phosphate mimics as feed for a predictive QSAR study on 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors
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DOI：
10.1002/cbdv.200890060
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发表时间：
2008-01-01
影响因子：
2.9
通讯作者：
Link, Andreas
中科院分区：
文献类型：
--
作者：
Giessmann, Dirk;Heidler, Philipp;Link, Andreas
1-脱氧-d -木酮糖-5-磷酸（DOXP）转化为2- c -甲基-d -赤藓糖-4-磷酸（MEP）被1-脱氧-d -木酮糖-5-磷酸还原异构酶（Dxr）抑制剂如天然抗生素fosmidomycin有效阻断。预测密切相关的Dxr配体的结合亲和力，以及估计这类不可水解磷酸盐模拟物中结构上更不同的抑制剂的亲和力，依赖于具有广泛靶标亲和力的fosmidomycin衍生物的合成。为了保持磷酸部分，对先导结构进行了线性修饰，以扩大这类具有物理化学挑战性的化合物的SAR。本文报道了一组磷酸的合成途径，其对大肠杆菌Dxr和恶性疟原虫Dxr的抑制活性（IC50）分别在1 ~ 30 μ M和0.4 ~ 20 μ M之间。
The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligands as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC50) in the range from 1 to >30 mu M vs. E. coli Dxr and 0.4 to 20 mu M against P. falciparum Dxr is reported.