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

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 this study, we discussed the syntheses of two novel heterocylic compounds: -butyl -4-(((3,4)-3-(1-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (-) and -(3,4)-3-(1-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2)-one (-), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound - showed higher anti-SARS-CoV-2 activity than -, with a half maximal effective concentration (EC) 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 - efficiently inhibited viral replication (EC = 2.78 μM; SI: > 71.94) and performed better than CQ (EC = 44.90 μM; SI = 2.94). The time of an addition assay showed that the action mechanism of - 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.