10.1021/acs.joc.8b00686.s001
David Bartee
David
Bartee
Michael J. Wheadon
Michael J.
Wheadon
Caren L. Freel Meyers
Caren
L. Freel Meyers
Synthesis and Evaluation
of Fluoroalkyl Phosphonyl
Analogues of 2‑<i>C</i>‑Methylerythritol Phosphate
as Substrates and Inhibitors of IspD from Human Pathogens
American Chemical Society
2018
Human Pathogens Targeting
antimetabolite alternative substrates
monofluoro MEP analogue displays
diphosphate
falciparum IspD orthologues
series
phosphonyl analogues
novel antimicrobial agents
IDP
DMADP
pathogen
Fluoroalkyl Phosphonyl Analogues
Escherichia coli IspD
inhibitor
phosphonyl MEP antimetabolites
MEP pathway intermediates
isoprenoid
orthogonal methylerythritol phosphate
2018-06-05 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Synthesis_and_Evaluation_of_Fluoroalkyl_Phosphonyl_Analogues_of_2_i_C_i_Methylerythritol_Phosphate_as_Substrates_and_Inhibitors_of_IspD_from_Human_Pathogens/6478946
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 <i>Plasmodium falciparum</i> and <i>Mycobacterium tuberculosis</i>, 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 <i>S</i>-monofluoro MEP analogue displays the most potent inhibitory activity
against <i>Escherichia coli</i> IspD and is the best substrate
for both the <i>E. coli</i> and <i>P. falciparum</i> IspD orthologues with a <i>K</i><sub>m</sub> approaching
that of the natural substrate for the <i>E. coli</i> enzyme.
This work represents a first step toward the development of phosphonyl
MEP antimetabolites to modulate early isoprenoid biosynthesis in human
pathogens.