In Mycobacterium tuberculosis (Mtb) and Plasmodium falciparum (Pf), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. The process and its products are vital to bacterial/parasitic metabolism. This pathway represents an attractive set of drug targets due to its essentiality in these pathogens but non-essentiality 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, however they lack the required lipophilicity to reach the desired target inside the cell. Synthesized FR900098 analogs with lipophilic substitution in the position a to the phosphorous atom showed promise, resulting in increased activity against Mtb and Pf. An a substitution, consisting of a 3,4-dichlorophenyl substituent, in combination with various O-linked alkylaryl substituents on the hydroxamate moiety is strategically 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 into the bi-substrate NADPH binding pocket, thus blocking the binding of NADPH. This series of FR900098 analogs includes diammonium salts and both diethyl and dipivaloyloxymethyl (POM) prodrug esters. Data from these compounds suggest that this combination of substituents is advantageous in designing a new generation of antimicrobials.

Natural product FR900098 analogs as small molecule inhibitors for the methylerythritol phosphate (MEP) pathway in mycobacterium tuberculosis (Mtb) and plasmodium falciparum (Pf)

ACS Spring Meeting 2021

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