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

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.