期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 37, 页码 13066-13079出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201907224
关键词
antimalarial agents; artemisinin; drug resistance; hybridization; proteomics
资金
- Deutsche Forschungsgemeinschaft (DFG) [TS 87/16-3]
- DFG (Gottfried Wilhelm Leibniz award)
- CSC
- Alexander von Humboldt foundation
- Interdisciplinary Center for Molecular Materials (ICMM)
- Graduate School Molecular Science (GSMS)
- Emerging Fields Initiative (EFI) Chemistry in Live Cells - Friedrich-Alexander-Universitat Erlangen-Nurnberg
- National Natural Science Foundation of China [81841001]
- Major National Science and Technology Program of China for Innovative Drug [2017ZX09101002-001-001-05]
- FAPESB (Brazil) [APP0088/2016]
- Fiocruz/Inova [1642178247]
- CNPq
- German Academic Exchange Service (DAAD)
A substantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs, such as chloroquine (CQ). To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)-based hybrids have been reported. Moreover, protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART-isoquinoline and ART-quinoline hybrids showing highly improved potencies against CQ-resistant and multidrug-resistant P. falciparum strains (EC50 (Dd2) down to 1.0 nm; EC50 (K1) down to 0.78 nm) compared to CQ (EC50 (Dd2)=165.3 nm; EC50 (K1)=302.8 nm) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step-economic C-H activation and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid-binding protein targets of the ART-quinolines were successfully identified in addition to known targets of quinoline and artemisinin alone, suggesting that the hybrids act through multiple modes of action to overcome resistance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据