Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb) are infectious microorganisms of particular interest, as these organisms infect millions worldwide. Unfortunately, both Pf and Mtb continually develop resistance to current drug therapies. Thus, resistance presents an imperative need to develop next-generation drugs to combat these infectious agents. One such approach is by inhibition of the non-mevalonate pathway (NMP), a pathway not found in humans. The NMP is responsible for the biosynthesis of five-carbon building blocks, called isoprenes. By inhibiting the NMP, isoprene biosynthesis in microorganisms is halted, and the growth and spread of the infectious agents are impeded. We aim to disrupt the NMP through inhibition of the enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), which is the first committed step of the pathway. In our prior work, an α,β-unsaturated lipophilic phosphonate prodrug, RCB-185, was shown to have potent activity against Pf. New analogs of RCB-185 are being synthesized in effort to understand the relationships between structure and in vitro/in vivo activities.

Synthesis of α,β-unsaturated phosphonate esters as DXR inhibitors

254th National Meeting (2017)

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