Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase

René Chofor, Sanjeewani Sooriyaarachchi, Martijn D P Risseeuw, Terese Bergfors, Jenny Pouyez, Chinchu Johny, Amanda Haymond, Annelien Everaert, Cynthia S. Dowd, Louis Maes, Tom Coenye, Alexander Alex, Robin D. Couch, T. Alwyn Jones, Johan Wouters, Sherry L. Mowbray, Serge Van Calenbergh

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Abstract

Blocking the 2-C-methyl-D-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. (Figure Presented).

Original languageEnglish
Pages (from-to)2988-3001
Number of pages14
JournalJournal of Medicinal Chemistry
Volume58
Issue number7
DOIs
Publication statusPublished - 9 Apr 2015

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Chofor, R., Sooriyaarachchi, S., Risseeuw, M. D. P., Bergfors, T., Pouyez, J., Johny, C., Haymond, A., Everaert, A., Dowd, C. S., Maes, L., Coenye, T., Alex, A., Couch, R. D., Jones, T. A., Wouters, J., Mowbray, S. L., & Van Calenbergh, S. (2015). Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase. Journal of Medicinal Chemistry, 58(7), 2988-3001. https://doi.org/10.1021/jm5014264