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

Abstract

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.

Hybrid Compounds Containing a Ferrocene Scaffold as Potential Antimalarials

“…However, its poor bioavailability has resulted in its use in combination with selected antimalarials [29,57,58] . The combination of artesunate with some antimalarials has been reported as an effective approach to overcome drug resistance [59,60] . The length of the linker also played an important role in the antimalarial activity of compounds 16 and 19 .…”

Steric and stereoscopic disulfide construction for cross-linkage via N-dithiophthalimides

“…Hybridization of diverse amino acids (5g), amino acid with uorescent molecules (5h), amino acid with saccharide (5i), and amino acid with nucleoside (5j) was all successfully established, providing possibilities to modify protein structures, improve pharmacological efficacy and overcome drug resistance. 25,26 Non-steroidal anti-inammatory drug indomethacin could be successfully crosslinked with antimalarial drug artesunate (5k) and anti-cancer drug podophyllotoxin (5l), which may serve as a dual-mode for the treatment of diseases.…”

Artemisinins as Anticancer Drugs: Novel Therapeutic Approaches, Molecular Mechanisms, and Clinical Trials

“…Pharmacophore hybridization, a classical medicinal chemistry approach, involves combination of two or more functional groups via covalent bonds to produce a novel compound holding preferable biological activities ( Meunier, 2008 ; Muregi and Ishih, 2010 ; Capci et al, 2019 ). This approach is often used in searching for safe, effective and specific innovative medicines for cancer therapy ( Letis et al, 2017 ; Yu et al, 2018 ; Zborovskii et al, 2018 ).…”