Amino acid based prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents
Amino acid based prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents
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DOI：
10.1016/j.bmc.2019.01.016
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Van Calenbergh, Serge
中科院分区：
文献类型：
--
作者：
Courtens, Charlotte;Risseeuw, Martijn;Van Calenbergh, Serge
磷霉素是一种天然抗生素，具有潜在的IspC(DXR，1-脱氧-D-木硫糖-5-磷酸还原异构酶)抑制活性。这种酶催化非甲氧戊酸类异戊二烯生物合成途径的第一步，这在恶性疟原虫和结核分枝杆菌中是必不可少的。主要是由于它的高极性，磷霉素表现出次佳的药代动力学特性。此外，由于它不能穿透细菌细胞壁，所以对结核分枝杆菌不起作用。暂时将磷酸盐部分作为前药进行掩盖，有可能解决这两个问题。我们报告了两种基于氨基酸的前药途径在一种磷霉素类替代品上的应用。将磷酸盐部分转化为酪氨酸衍生的酯可提高体外抗恶性疟原虫无性血期的活性，而磷二酸酯前药显示出良好的抗结核活性。选定的前药在伯氏疟原虫小鼠模型中进行了活体测试。这些结果表明在体内具有良好的抗疟原虫能力。
Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-D-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential.