Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase
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.
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.
Show others and affiliations
2015 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 7, 2988-3001 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 58, no 7, 2988-3001 p.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-252687DOI: 10.1021/jm5014264ISI: 000353091300006PubMedID: 25781377OAI: oai:DiVA.org:uu-252687DiVA: diva2:813987
Funder
Swedish Research Council FormasSwedish Research Council
Available from: 2015-05-25 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved

Open Access in DiVA

fulltext(1968 kB)48 downloads
File information
File name FULLTEXT01.pdfFile size 1968 kBChecksum SHA-512
e3c48032bc1f6908139f89f2187c3be5257a7f9d9122fbbb5f0379a20d2ffaeb3f64fb1b55537352c11be2632f4c3f68283fbf4590d441b43364ebd837666440
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Sooriyaarachchi, SanjeewaniBergfors, TereseJones, T. AlwynMowbray, Sherry L.
By organisation
Structure and Molecular BiologyScience for Life Laboratory, SciLifeLab
In the same journal
Journal of Medicinal Chemistry
Medicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 48 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 639 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf