Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues

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Abstract

The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells.
Original languageEnglish
Pages (from-to)2112-2116
Number of pages5
JournalBioorganic & Medicinal Chemistry Letters
Volume25
Issue number10
DOIs
Publication statusPublished - 15 May 2015

Keywords

  • Antimalarial
  • Fosmidomycin
  • Hydroxamates
  • Phosphonates
  • Phospha-Michael
  • FALCIPARUM GROWTH-INHIBITORS
  • PLASMODIUM-FALCIPARUM
  • BIOLOGICAL EVALUATION
  • ESTER PRODRUGS
  • CARBONYL-COMPOUNDS
  • ORGANIC-SYNTHESIS
  • FR900098
  • MALARIA
  • BIOSYNTHESIS
  • PHOSPHONATES

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