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

Fröhlich T, Hahn F, Belmudes L, Leidenberger M, Friedrich O, Kappes B, Coute Y, Marschall M, Tsogoeva S (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 24

Pages Range: 8103-8113

Journal Issue: 32

DOI: 10.1002/chem.201800729

Abstract

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 mu m, representing an even higher activity than the two reference drugs ganciclovir (EC50 2.60 mu m) and artesunic acid (EC50 5.41 mu m). 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.

Authors with CRIS profile

Involved external institutions

University of Grenoble Alpes (UGA) / Université de Grenoble France (FR)

How to cite

APA:

Fröhlich, T., Hahn, F., Belmudes, L., Leidenberger, M., Friedrich, O., Kappes, B.,... Tsogoeva, S. (2018). Synthesis of Artemisinin-Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action. Chemistry - A European Journal, 24(32), 8103-8113. https://dx.doi.org/10.1002/chem.201800729

MLA:

Fröhlich, Tony, et al. "Synthesis of Artemisinin-Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action." Chemistry - A European Journal 24.32 (2018): 8103-8113.

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