Alpha-Heteroatorn Derivatized Analogues of 3-(Acetylhydroxyamino)propyl Phosphonic Acid (FR900098) as Antimalarials
Alpha-Heteroatorn Derivatized Analogues of 3-(Acetylhydroxyamino)propyl Phosphonic Acid (FR900098) as Antimalarials
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DOI：
10.1021/jm301577q
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发表时间：
2013-01-10
影响因子：
7.3
通讯作者：
Van Calenbergh, Serge
中科院分区：
文献类型：
--
作者：
Verbrugghen, Thomas;Vandurm, Pierre;Van Calenbergh, Serge
为了探索磷霉素α-碳的成功衍生化，制备了一系列新的α-取代类似物。这是通过在膦酸酯的α-位引入杂原子（N或O）并使用所得OH和NH 2基团作为通过几个官能团如醚、酰胺、脲和1，4-三唑附加各种取代基的柄来完成的。测定作为外消旋混合物的合成分子的EcDXR抑制效力。α-叠氮基类似物和α-羟基化类似物证明是最有前途的，并进行对接实验。尽管几种化合物在人红细胞中测定抗恶性疟原虫K1时显示出高效力，但未发现酶抑制常数与恶性疟原虫抑制浓度之间存在明确的相关性。
To explore the hitherto successful derivatization of the alpha-carbon of fosmidomycin, a series of new a-substituted analogues was prepared. This was done by introduction of a heteroatom (N or O) in alpha-position to the phosphonate and using the resultant OH and NH2 groups as a handle for appending a variety of substituents by means of several functional groups such as ether, amide, urea, and 1,4-triazole. The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory potency. Both the alpha-azido-analogue and the alpha-hydroxylated analogue proved most promising, and docking experiments were performed. Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not be found.