MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

Xu Wang, Rachel L. Edwards, Haley Ball, Claire Johnson, Amanda Haymond, Misgina Girma, Michelle Manikkam, Robert C. Brothers, Kyle T. McKay, Stacy D. Arnett, Damon M. Osbourn, Sophie Alvarez, Helena I. Boshoff, Marvin J. Meyers, Robin D. Couch, Audrey R. Odom John, Cynthia S. Dowd

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans. In this study, we designed and synthesized a series of α,β-unsaturated analogues of fosmidomycin, a natural product that inhibits DXR in P. falciparum. All compounds were evaluated as inhibitors of P. falciparum. The most promising compound, 18a, displays on-target, potent inhibition against the growth of P. falciparum (IC50 = 13 nM) without significant inhibition of HepG2 cells (IC50 > 50 μM). 18a was also tested in a luciferase-based Plasmodium berghei mouse model of malaria and showed exceptional in vivo efficacy. Together, the data support MEPicide 18a as a novel, potent, and promising drug candidate for the treatment of malaria.

Original languageEnglish (US)
Pages (from-to)8847-8858
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number19
DOIs
StatePublished - Oct 11 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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