文献类型：期刊文献

英文题名：Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely

作者：Chen, Wenhua[1];Huang, Zhenghui[2];Wang, Wanyan[1];Mao, Fei[1];Guan, Longfei[1];Tang, Yun[1];Jiang, Hualiang[1];Li, Jian[1];Huang, Jin[1];Jiang, Lubin[2];Zhu, Jin[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Univ Chinese Acad Sci, Inst Pasteur Shanghai, Unit Human Parasite Mol & Cell Biol, Key Lab Mol Virol & Immunol, 320 Yueyang Rd, Shanghai 200031, Peoples R China

年份：2017

卷号：25

期号：24

起止页码：6467

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000415984900021)】；

基金：Financial support for this research provided by the National Natural Science Foundation of China (Grants 21372001 and 21672064), the "Shu Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (Grant 14SG28), and the Fundamental Research Funds for the Central Universities are gratefully acknowledged.

语种：英文

外文关键词：Antimalarial drug; Plasmodium falciparum; FP-2; PfDHFR; Dual inhibitor

摘要：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 mu M), 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. (C) 2017 Elsevier Ltd. All rights reserved.