MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

J Med Chem. 2018 Oct 11;61(19):8847-8858. doi: 10.1021/acs.jmedchem.8b01026. Epub 2018 Sep 24.


Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans. In this study, we designed and synthesized a series of α,β-unsaturated analogues of fosmidomycin, a natural product that inhibits DXR in P. falciparum. All compounds were evaluated as inhibitors of P. falciparum. The most promising compound, 18a, displays on-target, potent inhibition against the growth of P. falciparum (IC50 = 13 nM) without significant inhibition of HepG2 cells (IC50 > 50 μM). 18a was also tested in a luciferase-based Plasmodium berghei mouse model of malaria and showed exceptional in vivo efficacy. Together, the data support MEPicide 18a as a novel, potent, and promising drug candidate for the treatment of malaria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Animals
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Female
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / chemistry
  • Fosfomycin / pharmacology
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / enzymology
  • Malaria, Falciparum / parasitology
  • Mice
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / growth & development*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Structure-Activity Relationship


  • Antimalarials
  • Prodrugs
  • Fosfomycin
  • fosmidomycin
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases