(Iso)Quinoline–Artemisinin Hybrids Prepared through Click Chemistry: Highly Potent Agents against Viruses

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). Combined strength: A series of (iso)quinoline–artemisinin hybrids are synthesized through click reactions and studied for their potency against human cytomegalovirus (HCMV). Seven hybrids show high in vitro activity and are more active than their parent compounds. Additionally, the most potent anti‐HCMV hybrid also shows inhibition activity against hepatitis B virus in vitro.