The methylerythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms including Plasmodium falciparum. One highly conserved enzyme in the MEP pathway is 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF). Inhibitors of IspF may result in potential anti-malarial activity with minimal host toxicity. Fragment based screening of IspF from Burkholderia pseudomallei yielded a co-crystalline structure of FOL955. Imidazole analogs of FOL955 have been synthesized and X-ray crystal structure of an analog was obtained and used for computational modeling. The ability of compounds to inhibit IspF was determined by SPR (surface plasma resonance) and anti-malarial activity was obtained at Walter Reed Amy Institute of Research.

Discovery of imidazole based IspF inhibitors

246th National Meeting (2013)

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