Novel Tetrahydroisoquinoline-Based Heterocyclic Compounds Efficiently Inhibit SARS-CoV-2 Infection In Vitro .

The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro . In this study, we discussed the syntheses of two novel heterocylic compounds: tert -butyl rel -4-(((3 R ,4 S )-3-(1 H -indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate ( trans - 1 ) and rel -(3 R ,4 S )-3-(1 H -indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2 H )-one ( trans - 2 ), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans - 1 showed higher anti-SARS-CoV-2 activity than trans - 2 , with a half maximal effective concentration (EC 50 ) of 3.15 μM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans - 1 efficiently inhibited viral replication (EC 50 = 2.78 μM; SI: > 71.94) and performed better than CQ (EC 50 = 44.90 μM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans - 1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed.