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Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase

René Chofor, Sanjeewani Sooriyaarachchi, Martijn Risseeuw UGent, Terese Bergfors, Jenny Pouyez, Chinchu Johny, Amanda Haymond, Annelien Everaert, Cynthia S Dowd, Louis Maes, et al. (2015) JOURNAL OF MEDICINAL CHEMISTRY. 58(7). p.2988-3001
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 beta-position of the hydroxamate analogue of 2. While direct addition of a beta-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 hydroxamates 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.
Please use this url to cite or link to this publication:
author
organization
alternative title
Synthesis and bioactivity of beta-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase
year
type
journalArticle (original)
publication status
published
subject
keyword
PLASMODIUM-FALCIPARUM MALARIA, 5-PHOSPHATE REDUCTOISOMERASE, METHYLERYTHRITOL PHOSPHATE-PATHWAY, ISOPRENOID BIOSYNTHESIS, MYCOBACTERIUM-TUBERCULOSIS, NONMEVALONATE PATHWAY, TERPENOID BIOSYNTHESIS, ANTIMALARIAL-DRUG, ESCHERICHIA-COLI, DXR INHIBITION
journal title
JOURNAL OF MEDICINAL CHEMISTRY
J. Med. Chem.
volume
58
issue
7
pages
2988 - 3001
Web of Science type
Article
Web of Science id
000353091300006
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
5.589 (2015)
JCR rank
3/59 (2015)
JCR quartile
1 (2015)
ISSN
0022-2623
DOI
10.1021/jm5014264
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
5957369
handle
http://hdl.handle.net/1854/LU-5957369
date created
2015-05-19 07:59:45
date last changed
2016-12-19 15:43:06
@article{5957369,
  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 beta-position of the hydroxamate analogue of 2. While direct addition of a beta-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 hydroxamates 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.},
  author       = {Chofor, Ren{\'e} and Sooriyaarachchi, Sanjeewani and Risseeuw, Martijn and Bergfors, Terese and Pouyez, Jenny and Johny, Chinchu and Haymond, Amanda and Everaert, Annelien and Dowd, Cynthia S and Maes, Louis and Coenye, Tom and Alex, Alexander and Couch, Robin D and Jones, T Alwyn and Wouters, Johan and Mowbray, Sherry L and Van Calenbergh, Serge},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {PLASMODIUM-FALCIPARUM MALARIA,5-PHOSPHATE REDUCTOISOMERASE,METHYLERYTHRITOL PHOSPHATE-PATHWAY,ISOPRENOID BIOSYNTHESIS,MYCOBACTERIUM-TUBERCULOSIS,NONMEVALONATE PATHWAY,TERPENOID BIOSYNTHESIS,ANTIMALARIAL-DRUG,ESCHERICHIA-COLI,DXR INHIBITION},
  language     = {eng},
  number       = {7},
  pages        = {2988--3001},
  title        = {Synthesis and bioactivity of \ensuremath{\beta}-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase},
  url          = {http://dx.doi.org/10.1021/jm5014264},
  volume       = {58},
  year         = {2015},
}

Chicago
Chofor, René, Sanjeewani Sooriyaarachchi, Martijn Risseeuw, Terese Bergfors, Jenny Pouyez, Chinchu Johny, Amanda Haymond, et al. 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.
APA
Chofor, R., Sooriyaarachchi, S., Risseeuw, M., Bergfors, T., Pouyez, J., Johny, C., Haymond, A., et al. (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.
Vancouver
1.
Chofor R, Sooriyaarachchi S, Risseeuw M, Bergfors T, Pouyez J, Johny C, et al. Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase. JOURNAL OF MEDICINAL CHEMISTRY. 2015;58(7):2988–3001.
MLA
Chofor, René, Sanjeewani Sooriyaarachchi, Martijn Risseeuw, et al. “Synthesis and Bioactivity of Β-substituted Fosmidomycin Analogues Targeting 1-deoxy-D-xylulose-5-phosphate Reductoisomerase.” JOURNAL OF MEDICINAL CHEMISTRY 58.7 (2015): 2988–3001. Print.