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Design, Synthesis, and Biological Evaluation of Phosphonate Antibiotics and Antimalarials Targeting the Non-Mevalonate Pathway in Mycobacterium tuberculosis and Plasmodium falciparium and the Phosphonic Acid Analogs as Inhibitors for 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Open Access

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According to the World Health Organization, the increasing prevalence of drug resistant microorganisms is a tremendous threat to modern society. Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), and Plasmodium falciparum (Pf), the parasite that causes malaria, are of particular concern. Due to increasing drug resistance, there is a significant need for new medications. One attractive target for drug design is the Non-Mevalonate Pathway (NMP) of isoprene biosynthesis. The first committed enzyme of this pathway, 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), has been the focus of recent efforts. Natural products fosmidomycin and FR900098 are potent Dxr inhibitors with limited antimicrobial activity. We are interested in assessing the inhibition of Dxr using β-substituted FR900098 analogs. We explored new synthetic routes to obtain the β-hydroxyl FR900098, natural product FR33289, and other β-substituted phosphonic acids. Additionally, we synthesized lipophilic phosphonate prodrug analogs with similar modified backbone structures. These compounds proved to be extremely potent antimicrobial agents. One compound, RCB-185, has low nanomolar antimalarial activity and was studied extensively.

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