Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91054, Erlangen, Germany.
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077, Göttingen, Germany.
Angew Chem Int Ed Engl. 2019 Sep 9;58(37):13066-13079. doi: 10.1002/anie.201907224. Epub 2019 Aug 8.
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 (EC (Dd2) down to 1.0 nm; EC (K1) down to 0.78 nm) compared to CQ (EC (Dd2)=165.3 nm; EC (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.
全世界都面临着一个重大挑战，即疟原虫对已批准药物（如氯喹）产生了耐药性。为了解决这些未解决的氯喹耐药问题，仅报道了少数基于青蒿素（ART）的杂合物。此外，这些杂合物的蛋白靶标尚未确定，其优越疗效的原因仍不清楚。在此，我们报告了新型 ART-异喹啉和 ART-喹啉杂合物的合成，与氯喹（EC （Dd2）为 165.3nm；EC （K1）为 302.8nm）相比，这些杂合物对氯喹耐药和多药耐药的 P. falciparum 株（EC （Dd2）低至 1.0nm；EC （K1）低至 0.78nm）具有显著提高的活性，并强烈抑制实验性疟疾中的寄生虫血症。这些新化合物可以通过经济高效的 C-H 活化和铜（I）催化叠氮-炔环加成（CuAAC）点击反应轻易获得。通过化学蛋白质组学，除了单独的喹啉和青蒿素的已知靶标外，还成功鉴定出 ART-喹啉的潜在杂合结合蛋白靶标，表明这些杂合物通过多种作用机制发挥作用以克服耐药性。
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