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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 Risseeuw UGent, Terese Bergfors, Jenny Pouyez, Cynthia S Dowd, Louis Maes, Johan Wouters, T Alwyn Jones, Serge Van Calenbergh UGent, et al. (2016) CHEMMEDCHEM. 11(18). p.2024-2036
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 -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.
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author
organization
alternative title
Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with -arylpropyl analogues of fosmidomycin
year
type
journalArticle (original)
publication status
published
subject
keyword
antibiotics, antiprotozoal agents, oxidoreductases, structural biology, structure-activity relationships, POTENTIAL ANTIINFECTIVE AGENTS, ISOPRENOID BIOSYNTHESIS, 5-PHOSPHATE REDUCTOISOMERASE, NONMEVALONATE PATHWAY, TERPENOID BIOSYNTHESIS, ANTIMALARIAL-DRUGS, MEP PATHWAY, INHIBITORS, MEVALONATE, MALARIA
journal title
CHEMMEDCHEM
ChemMedChem
volume
11
issue
18
pages
2024 - 2036
Web of Science type
Article
Web of Science id
000383693800007
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
3.225 (2016)
JCR rank
17/60 (2016)
JCR quartile
2 (2016)
ISSN
1860-7179
DOI
10.1002/cmdc.201600249
language
English
UGent publication?
yes
classification
A1
additional info
the first two authors contributed equally to the study; the last two authors also contributed equally to the study
copyright statement
I have transferred the copyright for this publication to the publisher
id
8509194
handle
http://hdl.handle.net/1854/LU-8509194
date created
2017-02-13 10:00:54
date last changed
2017-10-02 22:30:26
@article{8509194,
  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 -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.},
  author       = {Sooriyaarachchi, Sanjeewani and Chofor, Ren{\'e} and Risseeuw, Martijn and Bergfors, Terese and Pouyez, Jenny and Dowd, Cynthia S and Maes, Louis and Wouters, Johan and Jones, T Alwyn and Van Calenbergh, Serge and Mowbray, Sherry L},
  issn         = {1860-7179},
  journal      = {CHEMMEDCHEM},
  keyword      = {antibiotics,antiprotozoal agents,oxidoreductases,structural biology,structure-activity relationships,POTENTIAL ANTIINFECTIVE AGENTS,ISOPRENOID BIOSYNTHESIS,5-PHOSPHATE REDUCTOISOMERASE,NONMEVALONATE PATHWAY,TERPENOID BIOSYNTHESIS,ANTIMALARIAL-DRUGS,MEP PATHWAY,INHIBITORS,MEVALONATE,MALARIA},
  language     = {eng},
  number       = {18},
  pages        = {2024--2036},
  title        = {Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with \ensuremath{\beta}-arylpropyl analogues of fosmidomycin},
  url          = {http://dx.doi.org/10.1002/cmdc.201600249},
  volume       = {11},
  year         = {2016},
}

Chicago
Sooriyaarachchi, Sanjeewani, René Chofor, Martijn Risseeuw, Terese Bergfors, Jenny Pouyez, Cynthia S Dowd, Louis Maes, et al. 2016. “Targeting an Aromatic Hotspot in Plasmodium Falciparum 1-deoxy-d-xylulose-5-phosphate Reductoisomerase with Β-arylpropyl Analogues of Fosmidomycin.” Chemmedchem 11 (18): 2024–2036.
APA
Sooriyaarachchi, S., Chofor, R., Risseeuw, M., Bergfors, T., Pouyez, J., Dowd, C. S., Maes, L., et al. (2016). Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with β-arylpropyl analogues of fosmidomycin. CHEMMEDCHEM, 11(18), 2024–2036.
Vancouver
1.
Sooriyaarachchi S, Chofor R, Risseeuw M, Bergfors T, Pouyez J, Dowd CS, et al. Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with β-arylpropyl analogues of fosmidomycin. CHEMMEDCHEM. 2016;11(18):2024–36.
MLA
Sooriyaarachchi, Sanjeewani, René Chofor, Martijn Risseeuw, et al. “Targeting an Aromatic Hotspot in Plasmodium Falciparum 1-deoxy-d-xylulose-5-phosphate Reductoisomerase with Β-arylpropyl Analogues of Fosmidomycin.” CHEMMEDCHEM 11.18 (2016): 2024–2036. Print.