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

doi:10.1021/acs.jmedchem.8b01026

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

Division of Infectious Disease

Research output: Contribution to journal › Article › peer-review

31 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 language	English
Pages (from-to)	8847-8858
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	19
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01026
State	Published - Oct 11 2018

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Wang, X., Edwards, R. L., Ball, H., Johnson, C., Haymond, A., Girma, M., Manikkam, M., Brothers, R. C., McKay, K. T., Arnett, S. D., Osbourn, D. M., Alvarez, S., Boshoff, H. I., Meyers, M. J., Couch, R. D., Odom John, A. R., & Dowd, C. S. (2018). MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria. Journal of Medicinal Chemistry, 61(19), 8847-8858. https://doi.org/10.1021/acs.jmedchem.8b01026

@article{01d6248db306405a96560d9fe8cafa6a,

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

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = oct,

day = "11",

doi = "10.1021/acs.jmedchem.8b01026",

language = "English",

volume = "61",

pages = "8847--8858",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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Wang, X, Edwards, RL, Ball, H, Johnson, C, Haymond, A, Girma, M, Manikkam, M, Brothers, RC, McKay, KT, Arnett, SD, Osbourn, DM, Alvarez, S, Boshoff, HI, Meyers, MJ, Couch, RD, Odom John, AR & Dowd, CS 2018, 'MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria', Journal of Medicinal Chemistry, vol. 61, no. 19, pp. 8847-8858. https://doi.org/10.1021/acs.jmedchem.8b01026

TY - JOUR

T1 - MEPicides

T2 - α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

AU - Wang, Xu

AU - Edwards, Rachel L.

AU - Ball, Haley

AU - Johnson, Claire

AU - Haymond, Amanda

AU - Girma, Misgina

AU - Manikkam, Michelle

AU - Brothers, Robert C.

AU - McKay, Kyle T.

AU - Arnett, Stacy D.

AU - Osbourn, Damon M.

AU - Alvarez, Sophie

AU - Boshoff, Helena I.

AU - Meyers, Marvin J.

AU - Couch, Robin D.

AU - Odom John, Audrey R.

AU - Dowd, Cynthia S.

PY - 2018/10/11

Y1 - 2018/10/11

N2 - 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.

AB - 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.

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DO - 10.1021/acs.jmedchem.8b01026

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SN - 0022-2623

VL - 61

SP - 8847

EP - 8858

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -

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

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