MEPicides: Design, Synthesis, and Evaluation of Novel Antimalarials
Open AccessMalaria, an ancient disease caused by Plasmodium parasites, continues to be one of the most severe infectious diseases worldwide. Traditional therapies are rapidly succumbing to drug resistance and a novel therapy with a new mechanism of action is gravely needed. Inhibition of isoprenoid biosynthesis has shown to be fatal to these parasites. Essential metabolites isopentenyl pyrophosphate and dimethylallyl pyrophosphate are biosynthetically obtained in Plasmodium spp. through use of the methylerythritol phosphate (MEP) pathway. The enzyme DXR catalyzes the first committed step. With no homolog and use of a different pathway to obtain these metabolites in humans, inhibition of DXR should allow for development of a drug that is relatively nontoxic while killing the parasites. In this work, we aim to develop novel antimalarial MEPicides through the design and synthesis of a series of prodrugs derivatized from fosmidomycin and FR900098, two natural product DXR inhibitors. Furthermore, a series of N-benzoyl fosmidomycin derivatives were also synthesized in an effort to explore structure-activity relationships around the N-acyl moiety of the molecule. Prodrugs of select N-acyl analogs were synthesized to be further evaluated in an animal model. Several compounds from both series demonstrate extraordinary antimalarial potency. The synthesis and biological evaluation of these analogs is presented here.
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