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J Med Chem. 2018 Oct 11;61(19):8847-8858. doi: 10.1021/acs.jmedchem.8b01026. Epub 2018 Sep 24.

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

Author information

1
Department of Chemistry , George Washington University , Washington D.C. 20052 , United States.
2
Department of Pediatrics , Washington University School of Medicine, Washington University , St. Louis , Missouri 63110 , United States.
3
Department of Chemistry and Biochemistry , George Mason University , Manassas , Virginia 20110 , United States.
4
Tuberculosis Research Section, LCIM , NIAID/NIH , Bethesda , Maryland 20892 , United States.
5
Department of Pharmacology and Physiology , Saint Louis University , St. Louis , Missouri 63104 , United States.
6
Department of Molecular Microbiology and Immunology , Saint Louis University , St. Louis , Missouri 63104 , United States.
7
Proteomics & Metabolomics Facility, Center for Biotechnology, Department of Agronomy and Horticulture , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States.
8
Department of Chemistry , Saint Louis University , St. Louis , Missouri 63103 , United States.

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.

PMID:
30192536
PMCID:
PMC6300130
[Available on 2019-10-11]
DOI:
10.1021/acs.jmedchem.8b01026

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