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Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2017-10-16 , DOI: 10.1016/j.bmc.2017.10.017
Wenhua Chen , Zhenghui Huang , Wanyan Wang , Fei Mao , Longfei Guan , Yun Tang , Hualiang Jiang , Jian Li , Jin Huang , Lubin Jiang , Jin Zhu

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 of 24, which showed high potency against FP-2 (IC50 = 10.0 µM), PfDHFR (IC50 = 84.1 nM), P. falciparum 3D7 (IC50 = 53.1 nM), clinical isolated strains Fab9 (IC50 = 14.2 nM) and GB4 (IC50 = 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.



中文翻译:

发现新的抗疟药:通过片段组装,第二代针对FP-2和PfDHFR的双重抑制剂

疟原虫是世界范围内因传染病致死的主要原因。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,这是绝对必要的。在这项研究中,基于已报道的PfDHFR抑制剂和第一代针对FP-2和PfDHFR的双重抑制剂的均一片段结构,我们通过片段组装鉴定了一系列新型的双重抑制剂。铅优化导致发现24种,对FP-2(IC 50  = 10.0 µM),PfDHFR(IC 50  = 84.1 nM),恶性疟原虫3D7(IC 50  = 53.1 nM),临床分离株Fab9表现出高效力(我知道了50  = 14.2 nM)和GB4(IC 50  = 23.4 nM)。在体内对抑制测定伯氏疟原虫在10天内显示24对生长的抑制更有利的影响伯氏疟原虫比青蒿素和乙胺嘧啶具有相同的效果。此外,24中度抑制耐氯喹的恶性疟原虫Dd2菌株的增殖。总体而言,这些数据表明,24可能是治疗疟疾的出色的铅化合物,如FP-2和PfDHFR双重抑制剂。

更新日期:2017-10-16
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