Synthetic Fosmidomycin analogues with altered chelating moieties do not inhibit 1-deoxy-d-xylulose 5-phosphate Reductoisomerase or Plasmodium falciparum growth in vitro

René Chofor; Martijn D P Risseeuw; Jenny Pouyez; Chinchu Johny; Johan Wouters; Cynthia S Dowd; Robin D Couch; Serge Van Calenbergh

doi:10.3390/molecules19022571

Synthetic Fosmidomycin analogues with altered chelating moieties do not inhibit 1-deoxy-d-xylulose 5-phosphate Reductoisomerase or Plasmodium falciparum growth in vitro

Molecules. 2014 Feb 24;19(2):2571-87. doi: 10.3390/molecules19022571.

Authors

René Chofor¹, Martijn D P Risseeuw², Jenny Pouyez³, Chinchu Johny⁴, Johan Wouters⁵, Cynthia S Dowd⁶, Robin D Couch⁷, Serge Van Calenbergh⁸

Affiliations

¹ Laboratory for Medicinal Chemistry, Ghent University, Harelbekestraat 72, Ghent B-9000, Belgium. rene.chofor@ugent.be.
² Laboratory for Medicinal Chemistry, Ghent University, Harelbekestraat 72, Ghent B-9000, Belgium. martijn.risseeuw@ugent.be.
³ Department of Chemistry, University of Namur, UNamur, Rue de Bruxelles 61, Namur B-5000, Belgium. jenny.pouyez@unamur.be.
⁴ Department of Chemistry and Biochemistry, George Mason University, Manassas, VA 20110, USA. cjohny@gmu.edu.
⁵ Department of Chemistry, University of Namur, UNamur, Rue de Bruxelles 61, Namur B-5000, Belgium. johan.wouters@unamur.be.
⁶ Department of Chemistry, George Washington University, Washington, DC 20052, USA. cdowd@gwu.edu.
⁷ Department of Chemistry and Biochemistry, George Mason University, Manassas, VA 20110, USA. rcouch@gmu.edu.
⁸ Laboratory for Medicinal Chemistry, Ghent University, Harelbekestraat 72, Ghent B-9000, Belgium. serge.vancalenbergh@ugent.be.

Abstract

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or the Plasmodia. This study further underlines the importance of the hydroxamate functionality and illustrates that identifying effective alternative bidentate ligands for this target enzyme is challenging.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldose-Ketose Isomerases / antagonists & inhibitors
Antimalarials / administration & dosage
Antimalarials / chemical synthesis
Antimalarials / chemistry
Drug Design
Enzyme Inhibitors / administration & dosage*
Enzyme Inhibitors / chemistry
Erythrocytes / drug effects*
Fosfomycin / administration & dosage
Fosfomycin / analogs & derivatives*
Fosfomycin / chemical synthesis
Humans
Plasmodium falciparum / drug effects*
Plasmodium falciparum / growth & development

Substances

Antimalarials
Enzyme Inhibitors
Fosfomycin
fosmidomycin
1-deoxy-D-xylulose 5-phosphate reductoisomerase
Aldose-Ketose Isomerases