MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria
| Autor: | 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 |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Plasmodium falciparum 030106 microbiology Pharmacology Article Antimalarials Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Fosfomycin In vivo parasitic diseases Drug Discovery medicine Animals Structure–activity relationship Prodrugs Plasmodium berghei Malaria Falciparum IC50 Aldose-Ketose Isomerases Natural product biology medicine.disease biology.organism_classification Fosmidomycin 030104 developmental biology chemistry Molecular Medicine Female Malaria medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 61:8847-8858 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01026 |
| Popis: | 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 (IC(50) = 13 nM) without significant inhibition of HepG2 cells (IC(50) > 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. |
| Databáze: | OpenAIRE |
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