Inhibition of DXR in the MEP pathway with lipophilic N-alkoxyaryl FR900098 analogsElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3md00642e

In Mycobacterium tuberculosis(Mtb) and Plasmodium falciparum(Pf), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. This pathway and its products are vital to bacterial/parasitic metabolism and survival, and represent an attractive set of drug targets due to their essentiality in these pathogens but absence in humans. The second step in the MEP pathway is the conversion of 1-deoxy-d-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR). Natural products fosmidomycin and FR900098 inhibit DXR, but are too polar to reach the desired target inside some cells, such as Mtb. Synthesized FR900098 analogs with lipophilic substitution in the position α to the phosphorous atom showed promise, resulting in increased activity against Mtband Pf. Here, an α substitution, consisting of a 3,4-dichlorophenyl substituent, in combination with various O-linked alkylaryl substituents on the hydroxamate moiety is utilized in the synthesis of a novel series of FR900098 analogs. The purpose of the O-linked alkylaryl substituents is to further enhance DXR inhibition by extending the structure into the adjacent NADPH binding pocket, blocking the binding of both DXP and NADPH. Of the initial O-linked alkylaryl substituted analogs, compound 6eshowed most potent activity against Pfparasites at 3.60 μM. Additional compounds varying the phenyl ring of 6ewere synthesized. The most potent phosphonic acids, 6land 6n, display nM activity against PfDXR and low μM activity against Pfparasites. Prodrugs of these compounds were less effective against Pfparasites but showed modest activity against Mtbcells. Data from this series of compounds suggests that this combination of substituents can be advantageous in designing a new generation of antimicrobials.