Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase

René Chofor, Sanjeewani Sooriyaarachchi, Martijn D P Risseeuw, Terese Bergfors, Jenny Pouyez, Chinchu Johny, Amanda Haymond, Annelien Everaert, Cynthia S. Dowd, Louis Maes, Tom Coenye, Alexander Alex, Robin D. Couch, T. Alwyn Jones, Johan Wouters, Sherry L. Mowbray, Serge Van Calenbergh

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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 β-position of the hydroxamate analogue of 2. While direct addition of a β-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 hydroxamate's 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. (Figure Presented).

langue originaleAnglais
Pages (de - à)2988-3001
Nombre de pages14
journalJournal of Medicinal Chemistry
Volume58
Numéro de publication7
Les DOIs
étatPublié - 9 avr. 2015

Empreinte digitale

Polyisoprenyl Phosphates
Mycobacterium smegmatis
Plasmodium
Enzymes
Plasmodium falciparum
Mycobacterium
Growth
Tryptophan
Parasites
Carbon
X-Rays
Escherichia coli
Ligands
fosmidomycin
1-deoxy-D-xylulose 5-phosphate reductoisomerase
In Vitro Techniques
tryptophanhydroxamate

Citer ceci

Chofor, René ; Sooriyaarachchi, Sanjeewani ; Risseeuw, Martijn D P ; Bergfors, Terese ; Pouyez, Jenny ; Johny, Chinchu ; Haymond, Amanda ; Everaert, Annelien ; Dowd, Cynthia S. ; Maes, Louis ; Coenye, Tom ; Alex, Alexander ; Couch, Robin D. ; Jones, T. Alwyn ; Wouters, Johan ; Mowbray, Sherry L. ; Van Calenbergh, Serge. / Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase. Dans: Journal of Medicinal Chemistry. 2015 ; Vol 58, Numéro 7. p. 2988-3001.
@article{902bbb4cec6e4ef9a893420e09be65c8,
title = "Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase",
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 β-position of the hydroxamate analogue of 2. While direct addition of a β-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 hydroxamate's 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. (Figure Presented).",
author = "Ren{\'e} Chofor and Sanjeewani Sooriyaarachchi and Risseeuw, {Martijn D P} and Terese Bergfors and Jenny Pouyez and Chinchu Johny and Amanda Haymond and Annelien Everaert and Dowd, {Cynthia S.} and Louis Maes and Tom Coenye and Alexander Alex and Couch, {Robin D.} and Jones, {T. Alwyn} and Johan Wouters and Mowbray, {Sherry L.} and {Van Calenbergh}, Serge",
year = "2015",
month = "4",
day = "9",
doi = "10.1021/jm5014264",
language = "English",
volume = "58",
pages = "2988--3001",
journal = "J. Med. Chem.",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

Chofor, R, Sooriyaarachchi, S, Risseeuw, MDP, Bergfors, T, Pouyez, J, Johny, C, Haymond, A, Everaert, A, Dowd, CS, Maes, L, Coenye, T, Alex, A, Couch, RD, Jones, TA, Wouters, J, Mowbray, SL & Van Calenbergh, S 2015, 'Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase', Journal of Medicinal Chemistry, VOL. 58, Numéro 7, p. 2988-3001. https://doi.org/10.1021/jm5014264

Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase. / Chofor, René; Sooriyaarachchi, Sanjeewani; Risseeuw, Martijn D P; Bergfors, Terese; Pouyez, Jenny; Johny, Chinchu; Haymond, Amanda; Everaert, Annelien; Dowd, Cynthia S.; Maes, Louis; Coenye, Tom; Alex, Alexander; Couch, Robin D.; Jones, T. Alwyn; Wouters, Johan; Mowbray, Sherry L.; Van Calenbergh, Serge.

Dans: Journal of Medicinal Chemistry, Vol 58, Numéro 7, 09.04.2015, p. 2988-3001.

Résultats de recherche: Contribution à un journal/une revueArticle

TY - JOUR

T1 - Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase

AU - Chofor, René

AU - Sooriyaarachchi, Sanjeewani

AU - Risseeuw, Martijn D P

AU - Bergfors, Terese

AU - Pouyez, Jenny

AU - Johny, Chinchu

AU - Haymond, Amanda

AU - Everaert, Annelien

AU - Dowd, Cynthia S.

AU - Maes, Louis

AU - Coenye, Tom

AU - Alex, Alexander

AU - Couch, Robin D.

AU - Jones, T. Alwyn

AU - Wouters, Johan

AU - Mowbray, Sherry L.

AU - Van Calenbergh, Serge

PY - 2015/4/9

Y1 - 2015/4/9

N2 - 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 β-position of the hydroxamate analogue of 2. While direct addition of a β-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 hydroxamate's 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. (Figure Presented).

AB - 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 β-position of the hydroxamate analogue of 2. While direct addition of a β-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 hydroxamate's 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. (Figure Presented).

UR - http://www.scopus.com/inward/record.url?scp=84927609709&partnerID=8YFLogxK

U2 - 10.1021/jm5014264

DO - 10.1021/jm5014264

M3 - Article

AN - SCOPUS:84927609709

VL - 58

SP - 2988

EP - 3001

JO - J. Med. Chem.

JF - J. Med. Chem.

SN - 0022-2623

IS - 7

ER -