Artemisinin and Quinoline Hybrid Compounds Inhibit Replication of SARS-CoV-2 In Vitro

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins (containing endoperoxide moiety) and chloroquine (containing quinoline subunit) against SARS-CoV-2 have recently been demonstrated, no study of artemisinin- and quinoline-based hybrids has been reported yet. However, the hybrid drug’s properties can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs. In this study, fifteen artemisinin- and quinoline-containing hybrid compounds were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 in a cytopathic effect reduction assay. All artesunic acid-containing hybrids display superior potency against SARS-CoV-2 (EC50 values 7.8 – 46 μM) and show low or no cytotoxic effects on Vero E6 cells (CC50 up to 110 µM). The most active artesunic acid-derived hybrid is significantly more potent in vitro (EC50 = 7.8 µM) than its parent compound artesunic acid (EC50 >50 µM). Among quinoline-based new compounds, quinoline-adamantane (EC50 = 1.5 μM) is the most efficient in vitro outperforming the reference drugs chloroquine (EC50 = 3.8 µM) and remdesivir (EC50 = 4.0 µM).