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

• Published in: Angewandte Chemie Vol. 131; no. 37; pp. 13200 - 13213
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 09-09-2019
• Subjects: Activation; Alkynes; Antimalaria-Wirkstoffe; Artemisinin; Chemical reactions; Chemical synthesis; Chemistry; Chloroquine; Cycloaddition; Drug resistance; Hybrids; Malaria; Multidrug resistance; Organic chemistry; Organic compounds; Parasite resistance; Parasitemia; Parasites; Proteins; Proteomics; Proteomik; Quinoline; Quinolines; Vector-borne diseases; Wirkstoff-Konjugate; Wirkstoff-Resistenz
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201907224

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.
Hybride auf Artemisinin‐Basis, die wirksam gegen CQ‐ und multiresistente Parasiten sind und eine starke Wirksamkeit bei experimenteller Malaria aufweisen, wurden synthetisiert. Durch chemische Proteomik wurden neue, möglicherweise hybridbindende Proteine zusätzlich zu den bekannten Zielproteinen von Chinolin und Artemisinin identifiziert, was darauf hindeutet, dass die Hybride mehrere Wirkmechanismen nutzen, um Resistenzen zu vermeiden.