Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin

Sanjeewani Sooriyaarachchi, René Chofor, Martijn D P Risseeuw, Terese Bergfors, Jenny Pouyez, Cynthia S. Dowd, Louis Maes, Johan Wouters, T. Alwyn Jones, Serge Van Calenbergh, Sherry L. Mowbray

Research output: Contribution to journalArticle

Abstract

Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.

Original languageEnglish
Pages (from-to)2024-2036
Number of pages13
JournalChemMedChem
DOIs
Publication statusPublished - 20 Sep 2016

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Keywords

  • antibiotics
  • antiprotozoal agents
  • oxidoreductases
  • structural biology
  • structure–activity relationships

Cite this

Sooriyaarachchi, S., Chofor, R., Risseeuw, M. D. P., Bergfors, T., Pouyez, J., Dowd, C. S., Maes, L., Wouters, J., Jones, T. A., Van Calenbergh, S., & Mowbray, S. L. (2016). Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin. ChemMedChem, 2024-2036. https://doi.org/10.1002/cmdc.201600249