alpha-Substituted beta-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation

作者：Bruecher Karin; Illarionov Boris; Held Jana; Tschan Serena; Kunfermann Andrea; Pein Miriam K; Bacher Adelbert; Graewert Tobias; Maes Louis; Mordmueller Benjamin; Fischer Markus; Kurz Thomas^*

来源：Journal of Medicinal Chemistry, 2012, 55(14): 6566-6575.

DOI：10.1021/jm300652f

Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. alpha-Aryl-substituted beta-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.

• 出版日期2012-7-26