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.