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Chemistry. 2018 Jun 7;24(32):8103-8113. doi: 10.1002/chem.201800729. Epub 2018 May 14.

Synthesis of Artemisinin-Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action.

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Organic Chemistry Chair I and Interdisciplinary Center for Molecular, Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058, Germany.
Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany.
Université Grenoble Alpes, CEA, INSERM, BIG-BGE, 38000, Grenoble, France.
Institute of Medical Biotechnology, Friedrich-Alexander University of Erlangen-Nürnberg, Paul-Gordon-Straße 3, 91052, Erlangen, Germany.


Generation of dimers, trimers and dendrimers of bioactive compounds is an approach that has recently been developed for the discovery of new potent drug candidates. Herein, we present the synthesis of new artemisinin-derived dimers and dendrimers and investigate their action against malaria parasite Plasmodium falciparum 3D7 strain and human cytomegalovirus (HCMV). Dimer 7 was the most active compound (EC50 1.4 nm) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC50 2.4 nm), artesunic acid (EC50 8.9 nm) and chloroquine (EC50 9.8 nm). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC50 value of 0.026 μm, representing an even higher activity than the two reference drugs ganciclovir (EC50 2.60 μm) and artesunic acid (EC50 5.41 μm). In addition, artemisinin-derived dimer 13 and trimer 15 were for the first time both immobilized on TOYOPEARL AF-Amino-650M beads and used for mass spectrometry-based target identification experiments using total lysates of HCMV-infected primary human fibroblasts. Two major groups of novel target candidates, namely cytoskeletal and mitochondrial proteins were obtained. Two putatively compound-binding viral proteins, namely major capsid protein (MCP) and envelope glycoprotein pUL132, which are both essential for HCMV replication, were identified.


antimalarial agents; dendrimers; drug design; drug discovery; proteomics

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