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Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with -Arylpropyl Analogues of Fosmidomycin
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Univ Ghent, Lab Med Chem FFW, Ottergemsesteenweg 460, B-9000 Ghent, Belgium..
Univ Ghent, Lab Med Chem FFW, Ottergemsesteenweg 460, B-9000 Ghent, Belgium..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 11, no 18, 2024-2036 p.Article in journal (Refereed) Published
Abstract [en]

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 -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.

Place, publisher, year, edition, pages
2016. Vol. 11, no 18, 2024-2036 p.
Keyword [en]
antibiotics, antiprotozoal agents, oxidoreductases, structural biology, structure-activity relationships
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-307755DOI: 10.1002/cmdc.201600249ISI: 000383693800007PubMedID: 27487410OAI: oai:DiVA.org:uu-307755DiVA: diva2:1048323
Funder
EU, European Research Council, 283570Swedish Research CouncilSwedish Research Council Formas
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2016-11-21Bibliographically approved

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