Malaria and tuberculosis infections are the most widespread infectious diseases in the world. Approximately eight million new cases of tuberculosis are diagnosed every year and 500,000 deaths worldwide are attributed to malaria every year. Tuberculosis infections are caused by the bacteria Mycobacterium tuberculosis (M. tuberculosis) while malaria is caused by the parasite Plasmodium falciparum (P. falciparum). Certain strains of both P. falciparum and M. tuberculosis have become highly resistant to a wide variety of current drugs therefore new antimalarial and antituberculosis drugs with novel modes of action are urgently needed. For several reasons, the 2C-methyl-D-erythritol-4-phosphate (MEP or non-mevalonate) pathway constitutes an attractive target for the development of new anti-infective agents. This pathway is not present in humans but only in pathogens such as bacteria, fungi and protozoa. Also, it is responsible for the biosynthesis of the isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) which play an important role in the life cycle of many pathogens. These isoprenoids are essential for the synthesis of the cell wall in M. tuberculosis and P. falciparum. Fosmidomycin is a potent, natural product inhibitor of the MEP pathway that acts via inhibition of the enzyme 1-deoxylulose-5-phosphate reductoisomerase (IspC). Despite potent in vitro activity against IspC, fosmidomycin is highly hydrophilic and has poor bioavailability thus limiting its use as a therapeutic. For these reasons, the overall goal of this work is the design of a library of fosmidomycin analogs with increased lipophilicity, to improve cellular penetration and bioavailability. All compounds will be evaluated as inhibitors of E.coli IspC. We will also investigate their ability to inhibit in vitro growth of E.coli and M. Smegmatis.

Synthesis of inhibitors of 1-deoxylulose- 5-phosphate reductoisomerase

2019 Spring National Meeting

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