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

Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Chemistry - A European Journal Wiley

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

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Publisher
Wiley
Copyright
© 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim
ISSN
0947-6539
eISSN
1521-3765
D.O.I.
10.1002/chem.201800729
Publisher site
See Article on Publisher Site

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 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.

Journal

Chemistry - A European JournalWiley

Published: Jan 7, 2018

Keywords: ; ; ; ;

References

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