伪-Substituted 尾-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation

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• 作者：Karin Br眉cher ; Boris Illarionov ; Jana Held ; Serena Tschan ; Andrea Kunfermann ; Miriam K. Pein ; Adelbert Bacher ; Tobias Gr盲wert ; Louis Maes ; Benjamin Mordm眉ller ; Markus Fischer ; Thomas Kurz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6566-6575
• 全文大小：433K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. 伪-Aryl-substituted 尾-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum. The most active derivative inhibits IspC protein of P. falciparum (PfIspC) with an IC₅₀ value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition in vitro.