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 mo

SUBMITTER: Wang X 

PROVIDER: S-EPMC6300130 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature