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.
N1 - Funding Information:
This work was generously supported by the George Washington University (GWU) Department of Chemistry, the GWU University Facilitating Fund, the NIH (AI 123433 to C.S.D. and AI 123808 to A.R.O.J.), and the Division of Intramural Research, NIAID, NIH. We thank Ana Rodriguez at the Anti-Infectives Screening core at NYU School of Medicine for testing the in vivo efficacy of 18e. We also thank Phil Mortimer (JHU) and Furong Sun (UIUC) for assistance with HRMS analysis. In vivo PK analysis was performed by Charles River Laboratories.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
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.
UR - http://www.scopus.com/inward/record.url?scp=85054137433&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01026
DO - 10.1021/acs.jmedchem.8b01026
M3 - Article
C2 - 30192536
AN - SCOPUS:85054137433
VL - 61
SP - 8847
EP - 8858
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 19
ER -