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Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria

Çapcı, Aysun ; Lorion, Mélanie M. ; Wang, Hui ; Simon, Nina ; Leidenberger, Maria ; Borges Silva, Mariana C. ; Moreira, Diogo R. M. ; Zhu, Yongping ; Meng, Yuqing ; Chen, Jia Yun ; Lee, Yew Mun ; Friedrich, Oliver ; Kappes, Barbara ; Wang, Jigang ; Ackermann, Lutz ; Tsogoeva, Svetlana B.

Angewandte Chemie (International ed.), 2019-09, Vol.58 (37), p.13066-13079 [Periódico revisado por pares]

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Título:
Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria
Autor: Çapcı, Aysun ; Lorion, Mélanie M. ; Wang, Hui ; Simon, Nina ; Leidenberger, Maria ; Borges Silva, Mariana C. ; Moreira, Diogo R. M. ; Zhu, Yongping ; Meng, Yuqing ; Chen, Jia Yun ; Lee, Yew Mun ; Friedrich, Oliver ; Kappes, Barbara ; Wang, Jigang ; Ackermann, Lutz ; Tsogoeva, Svetlana B.
Assuntos: Activation ; Alkynes ; Animals ; antimalarial agents ; Antimalarials - chemical synthesis ; Antimalarials - chemistry ; Antimalarials - pharmacology ; Antimalarials - therapeutic use ; Artemisinin ; Artemisinins - chemical synthesis ; Artemisinins - chemistry ; Artemisinins - pharmacology ; Artemisinins - therapeutic use ; Chemical reactions ; Chemical synthesis ; Chloroquine ; Click Chemistry ; Cycloaddition ; Drug resistance ; Drug Resistance, Multiple ; Humans ; hybridization ; Hybrids ; Isoquinolines - chemical synthesis ; Isoquinolines - chemistry ; Isoquinolines - pharmacology ; Isoquinolines - therapeutic use ; Malaria ; Malaria - drug therapy ; Mice ; Organic chemistry ; Organic compounds ; Parasite resistance ; Parasitemia ; Parasites ; Plasmodium - drug effects ; Proteins ; Proteomics ; Quinoline ; Quinolines ; Vector-borne diseases
É parte de: Angewandte Chemie (International ed.), 2019-09, Vol.58 (37), p.13066-13079
Notas: Dedicated to Professor Youyou Tu
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The copyright line for this article was changed on 5 November 2019 after original online publication.
Descrição: 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. ARTful hybrids: Artemisinin (ART)‐based hybrids that are highly potent against CQ/drug‐sensitive and multidrug‐resistant parasites and of strong efficacy in experimental malaria were synthesized. New putatively hybrid‐binding proteins, in addition to known target proteins of quinoline and artemisinin, were identified by chemical proteomics, suggesting that the hybrids act through multiple modes of action to overcome resistance.
Editor: Germany: Wiley Subscription Services, Inc
Idioma: Inglês

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Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria

Çapcı, Aysun ; Lorion, Mélanie M. ; Wang, Hui ; Simon, Nina ; Leidenberger, Maria ; Borges Silva, Mariana C. ; Moreira, Diogo R. M. ; Zhu, Yongping ; Meng, Yuqing ; Chen, Jia Yun ; Lee, Yew Mun ; Friedrich, Oliver ; Kappes, Barbara ; Wang, Jigang ; Ackermann, Lutz ; Tsogoeva, Svetlana B.

Germany: Wiley Subscription Services, Inc

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