(Iso)Quinoline-Artemisinin Hybrids via Click Chemistry: Highly Potent Agents against Viruses.

Viral infections cause life-threatening diseases in millions of people worldwide every year and there is 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 hybrid drug's properties compared to its parent compounds. In this study, (iso)quinoline-artemisinin hybrids, obtained via copper-catalyzed azide-alkyne cycloaddition (CuAAC) or organocatalyzed 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), as compared with their parent compounds and the reference drug ganciclovir. EC50 (HCMV) values were obtained in a range 0.22-1.20 µM, indicating 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 shows also inhibitory activity against hepatitis B virus in vitro (EC50 (HBeAg) = 2.57 µM).