Premium
Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action
Author(s) -
Fröhlich Tony,
Hahn Friedrich,
Belmudes Lucid,
Leidenberger Maria,
Friedrich Oliver,
Kappes Barbara,
Couté Yohann,
Marschall Manfred,
Tsogoeva Svetlana B.
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201800729
Subject(s) - artemisinin , dihydroartemisinin , trimer , chemistry , plasmodium falciparum , human cytomegalovirus , dimer , in vitro , biochemistry , biology , gene , organic chemistry , malaria , immunology
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 (EC 50 1.4 n m ) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC 50 2.4 n m ), artesunic acid (EC 50 8.9 n m ) and chloroquine (EC 50 9.8 n m ). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC 50 value of 0.026 μ m , representing an even higher activity than the two reference drugs ganciclovir (EC 50 2.60 μ m ) and artesunic acid (EC 50 5.41 μ 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.