Department of Chemistry , George Washington University , Washington D.C. 20052 , United States.
Department of Pediatrics , Washington University School of Medicine, Washington University , St. Louis , Missouri 63110 , United States.
J Med Chem. 2018 Oct 11;61(19):8847-8858. doi: 10.1021/acs.jmedchem.8b01026. Epub 2018 Sep 24.
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 = 13 nM) without significant inhibition of HepG2 cells (IC > 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.
严重疟疾仍然是全球重大健康威胁。二甲烯丙基焦磷酸合酶（DXR）是 MEP 途径中的第二种酶，对合成异戊烯基的构建块起着重要作用。由于其在疟原虫中的重要性及其在人类中的缺乏，这种酶是治疗疟疾的一个有前途的药物靶点。在这项研究中，我们设计并合成了一系列法舒地尔的α,β-不饱和类似物，法舒地尔是一种抑制疟原虫 DXR 的天然产物。所有化合物均被评估为对疟原虫的抑制剂。最有前途的化合物 18a 对 P. falciparum 的生长具有靶向、强效的抑制作用（IC = 13 nM），而对 HepG2 细胞没有显著抑制作用（IC > 50 μM）。18a 还在基于荧光素酶的伯氏疟原虫小鼠疟疾模型中进行了测试，显示出了极好的体内疗效。综上所述，数据支持 MEPicide 18a 作为一种新型、强效、有前途的抗疟疾药物候选物。
