Viral infections cause life-threatening diseases in millions of people worldwide every year and there is an urgent need for new, effective antiviral drugs. Hybridization of two chemically diverse compounds into a new bioactive effector product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds. In this study, (iso)quinoline-artemisinin hybrids, obtained through copper-catalyzed azide-alkyne cycloaddition or metal-free click reactions (in organic solvents or in the presence of water), were analyzed in vitro, for the first time, for their inhibitory activity against human cytomegalovirus (HCMV), relative to their parent compounds and the reference drug ganciclovir. EC50 (HCMV) values were obtained in a range 0.22-1.20 μm, which indicated highly potent antiviral properties in the absence of cytotoxic effects on normal cells (CC50 >100 μm). The most active hybrid, 1 (EC50 =0.22 μm), is 25 times more potent than its parent compound artesunic acid (EC50 =5.41 μm) and 12 times more efficient than the standard drug ganciclovir (EC50 =2.6 μm). Interestingly, hybrid 1 also shows inhibitory activity against hepatitis B virus in vitro (EC50 (HBeAg)=2.57 μm).

German Center for Cardiovascular Research Potsdamer Str 58 10785 Berlin Germany

Institut für Organische und Biomolekulare Chemie Georg August Universität Göttingen Tammannstraße 2 37077 Göttingen Germany

Institute for Clinical and Molecular Virology Friedrich Alexander University of Erlangen Nürnberg Schlossgarten 4 91054 Erlangen Germany

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo namesti 2 16610 Prague Czech Republic

Organic Chemistry Chair 1 and Interdisciplinary Center for Molecular Materials Friedrich Alexander University of Erlangen Nürnberg Nikolaus Fiebiger Straße 10 91058 Erlangen Germany

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Synthesis and in vitro Study of Artemisinin/Synthetic Peroxide-Based Hybrid Compounds against SARS-CoV-2 and Cancer