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.

恶性疟原虫（Plasmodium falciparum）引发的重型疟疾仍是一项重大的全球公共卫生威胁。DXR作为MEP途径中的第二种酶，在类异戊二烯的结构单元合成过程中发挥关键作用。由于该酶对疟原虫生存的必需性，且人类体内不存在该酶，它成为抗疟疾药物研发中极具潜力的靶点。本研究中，我们设计并合成了一系列磷胺霉素（fosmidomycin）的α,β-不饱和类似物；磷胺霉素是一种可抑制恶性疟原虫DXR活性的天然产物。我们对所有化合物的抗恶性疟原虫抑制活性进行了系统评估。其中最具潜力的化合物18a展现出靶向性的强效抗恶性疟原虫增殖活性（半数抑制浓度IC50=13 nM），且对HepG2细胞无显著抑制作用（IC50>50 μM）。此外，我们采用基于荧光素酶标记的伯氏疟原虫（Plasmodium berghei）小鼠疟疾感染模型对18a开展了体内药效测试，结果显示其体内抗疟药效优异。综上，本研究数据证实MEPicide 18a是一款新颖、强效且极具前景的抗疟疾候选药物。