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To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)\u2010based 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\u2013isoquinoline and ART\u2013quinoline hybrids showing highly improved potencies against CQ\u2010resistant and multidrug\u2010resistant <jats:italic>P.\u2005falciparum<\/jats:italic> strains (EC<jats:sub>50<\/jats:sub>\u2009(Dd2) down to 1.0\u2005n<jats:sc>m<\/jats:sc>; EC<jats:sub>50<\/jats:sub>\u2009(K1) down to 0.78\u2005n<jats:sc>m<\/jats:sc>) compared to CQ (EC<jats:sub>50<\/jats:sub>\u2009(Dd2)=165.3\u2005n<jats:sc>m<\/jats:sc>; EC<jats:sub>50<\/jats:sub>\u2009(K1)=302.8\u2005n<jats:sc>m<\/jats:sc>) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step\u2010economic C\u2212H activation and copper(I)\u2010catalyzed azide\u2013alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid\u2010binding protein targets of the ART\u2010quinolines 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.<\/jats:p>","DOI":"10.1002\/anie.201907224","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T08:23:06Z","timestamp":1562746986000},"page":"13066-13079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":102,"title":["Artemisinin\u2013(Iso)quinoline Hybrids by C\u2212H Activation and Click Chemistry: Combating Multidrug\u2010Resistant Malaria"],"prefix":"10.1002","volume":"58","author":[{"given":"Aysun","family":"\u00c7apc\u0131","sequence":"first","affiliation":[{"name":"Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM) Friedrich-Alexander University of Erlangen-N\u00fcrnberg  Nikolaus-Fiebiger-Stra\u00dfe 10 91054 Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-9103","authenticated-orcid":false,"given":"M\u00e9lanie M.","family":"Lorion","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Organische und Biomolekulare Chemie Georg-August-Universit\u00e4t G\u00f6ttingen  Tammannstra\u00dfe 2 37077 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0249-0432","authenticated-orcid":false,"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Organische und Biomolekulare Chemie Georg-August-Universit\u00e4t G\u00f6ttingen  Tammannstra\u00dfe 2 37077 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5189-8688","authenticated-orcid":false,"given":"Nina","family":"Simon","sequence":"additional","affiliation":[{"name":"Institute of Medical Biotechnology Friedrich-Alexander University of Erlangen-N\u00fcrnberg  Paul-Gordon-Stra\u00dfe 3 91052 Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Leidenberger","sequence":"additional","affiliation":[{"name":"Institute of Medical Biotechnology Friedrich-Alexander University of Erlangen-N\u00fcrnberg  Paul-Gordon-Stra\u00dfe 3 91052 Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana C.","family":"Borges\u2005Silva","sequence":"additional","affiliation":[{"name":"Fiocruz, Instituto Gon\u00e7alo Moniz, 40296-710  Salvador, BA Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3323-4404","authenticated-orcid":false,"given":"Diogo R. M.","family":"Moreira","sequence":"additional","affiliation":[{"name":"Fiocruz, Instituto Gon\u00e7alo Moniz, 40296-710  Salvador, BA Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Zhu","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center, and Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences  Beijing 100700 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Meng","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center, and Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences  Beijing 100700 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center, and Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences  Beijing 100700 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yew Mun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences National University of Singapore  117600 Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2238-2049","authenticated-orcid":false,"given":"Oliver","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Institute of Medical Biotechnology Friedrich-Alexander University of Erlangen-N\u00fcrnberg  Paul-Gordon-Stra\u00dfe 3 91052 Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kappes","sequence":"additional","affiliation":[{"name":"Institute of Medical Biotechnology Friedrich-Alexander University of Erlangen-N\u00fcrnberg  Paul-Gordon-Stra\u00dfe 3 91052 Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-0105","authenticated-orcid":false,"given":"Jigang","family":"Wang","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center, and Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences  Beijing 100700 China"},{"name":"Shenzhen People's Hospital  Shenzhen 518020 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7034-8772","authenticated-orcid":false,"given":"Lutz","family":"Ackermann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Organische und Biomolekulare Chemie Georg-August-Universit\u00e4t G\u00f6ttingen  Tammannstra\u00dfe 2 37077 G\u00f6ttingen Germany"},{"name":"German Center for Cardiovascular Research (DZHK)  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-0951","authenticated-orcid":false,"given":"Svetlana B.","family":"Tsogoeva","sequence":"additional","affiliation":[{"name":"Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM) Friedrich-Alexander University of Erlangen-N\u00fcrnberg  Nikolaus-Fiebiger-Stra\u00dfe 10 91054 Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,8]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"World Health Organization (2018) World Malaria Report 2018;http:\/\/www.who.int\/iris\/handle\/10665\/275867. 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