Novel Tetrahydroisoquinoline-Based Heterocyclic Compounds Efficiently Inhibit SARS-CoV-2 Infection <i>In Vitro</i>
2023
Xi Wang | Nikola T. Burdzhiev | Hengrui Hu | Yufeng Li | Jiang Li | Vesela V. Lozanova | Meglena I. Kandinska | Manli Wang
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 <i>in vitro</i>. In this study, we discussed the syntheses of two novel heterocylic compounds: <i>tert</i>-butyl <i>rel</i>-4-(((3<i>R</i>,4<i>S</i>)-3-(1<i>H</i>-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (<i>trans</i>-<b>1</b>) and <i>rel</i>-(3<i>R</i>,4<i>S</i>)-3-(1<i>H</i>-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2<i>H</i>)-one (<i>trans</i>-<b>2</b>), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound <i>trans</i>-<b>1</b> showed higher anti-SARS-CoV-2 activity than <i>trans</i>-<b>2</b>, with a half maximal effective concentration (EC<sub>50</sub>) 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 <i>trans</i>-<b>1</b> efficiently inhibited viral replication (EC<sub>50</sub> = 2.78 μM; SI: > 71.94) and performed better than CQ (EC<sub>50</sub> = 44.90 μM; SI = 2.94). The time of an addition assay showed that the action mechanism of <i>trans</i>-<b>1</b> 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.
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