Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely.
Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely.
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DOI：
10.1016/j.bmc.2017.10.017
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发表时间：
2017-12
影响因子：
3.5
通讯作者：
Wenhua Chen;Zhenghui Huang;Wanyan Wang;Fei Mao;Longfei Guan;Yun Tang;Hualiang Jiang;Jian Li;Jin Huang;Lubing Jiang;Jin Zhu
中科院分区：
文献类型：
--
作者：
Wenhua Chen;Zhenghui Huang;Wanyan Wang;Fei Mao;Longfei Guan;Yun Tang;Hualiang Jiang;Jian Li;Jin Huang;Lubing Jiang;Jin Zhu
疟疾寄生虫是全世界传染病死亡的主要原因。半胱氨酸蛋白酶falcipain-2（FP-2）和恶性疟原虫二氢叶酸还原酶（PfDHFR）在寄生虫的生命周期中起着至关重要的作用。本研究基于已报道的PfDHFR抑制剂和第一代FP-2和PfDHFR双重抑制剂的均一片段结构，通过片段组装鉴定了一系列新型双重抑制剂。先导物优化导致发现了24，其对FP-2（IC 50 = 10.0 µM）、PfDHFR（IC 50 = 84.1 nM）、恶性疟原虫3D 7（IC 50 = 53.1 nM）、临床分离菌株Fab 9（IC 50 = 14.2 nM）和GB 4（IC 50 = 23.4 nM）显示出高效力。体内抑制试验表明，bergheiin 10 d表明24对P. bergheithan青蒿素和相同的效果与乙胺嘧啶。此外，24对氯喹抗性P. Dd 2株。总之，这些数据表明，24可以作为FP-2和PfDHFR双重抑制剂用于治疗疟疾的优良先导化合物。
Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of24, which showed high potency against FP-2 (IC50= 10.0 µM), PfDHFR (IC50= 84.1 nM),P. falciparum3D7 (IC50= 53.1 nM), clinical isolated strains Fab9 (IC50= 14.2 nM) and GB4 (IC50= 23.4 nM). Thein vivoinhibition assays againstP. bergheiin 10 days indicated24had a more beneficial effect on the growth inhibition ofP. bergheithan artemisinin and an identical effect with pyrimethamine. Additionally,24moderately inhibited the proliferation of chloroquine-resistantP. falciparumDd2 strain. Collectively, these data revealed that24could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.