Synthesis and Evaluation of Fluoroalkyl Phosphonyl Analogues of 2- C-Methylerythritol Phosphate as Substrates and Inhibitors of IspD from Human Pathogens

J Org Chem. 2018 Sep 7;83(17):9580-9591. doi: 10.1021/acs.joc.8b00686. Epub 2018 Jun 11.


Targeting essential bacterial processes beyond cell wall, protein, nucleotide, and folate syntheses holds promise to reveal new antimicrobial agents and expand the potential drugs available for combination therapies. The synthesis of isoprenoid precursors, isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), is vital for all organisms; however, humans use the mevalonate pathway for production of IDP/DMADP while many pathogens, including Plasmodium falciparum and Mycobacterium tuberculosis, use the orthogonal methylerythritol phosphate (MEP) pathway. Toward developing novel antimicrobial agents, we have designed and synthesized a series of phosphonyl analogues of MEP and evaluated their abilities to interact with IspD, both as inhibitors of the natural reaction and as antimetabolite alternative substrates that could be processed enzymatically to form stable phosphonyl analogues as potential inhibitors of downstream MEP pathway intermediates. In this compound series, the S-monofluoro MEP analogue displays the most potent inhibitory activity against Escherichia coli IspD and is the best substrate for both the E. coli and P. falciparum IspD orthologues with a Km approaching that of the natural substrate for the E. coli enzyme. This work represents a first step toward the development of phosphonyl MEP antimetabolites to modulate early isoprenoid biosynthesis in human pathogens.

Publication types

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

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / chemistry
  • Aldose-Ketose Isomerases / metabolism*
  • Alkylation
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Erythritol / analogs & derivatives*
  • Erythritol / chemical synthesis
  • Erythritol / chemistry
  • Erythritol / metabolism
  • Erythritol / pharmacology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism*
  • Humans
  • Models, Molecular
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / chemistry
  • Multienzyme Complexes / metabolism*
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Oxidoreductases / metabolism*
  • Stereoisomerism


  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Multienzyme Complexes
  • 3-C-methylerythritol
  • Oxidoreductases
  • IspD protein, E coli
  • Aldose-Ketose Isomerases
  • Erythritol