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

Viruses. 2023 Feb 11;15(2):502. doi: 10.3390/v15020502.

Abstract

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-(((3R,4S)-3-(1H-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (trans-1) and rel-(3R,4S)-3-(1H-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2H)-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 (EC50) 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 (EC50 = 2.78 μM; SI: > 71.94) and performed better than CQ (EC50 = 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.

Keywords: 1,2,3,4-tetrahydroisoquinoline; SARS-CoV-2; antivirals; chloroquine; indole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • COVID-19*
  • Chloroquine / pharmacology
  • Heterocyclic Compounds*
  • Humans
  • Hydroxychloroquine / pharmacology
  • Pandemics
  • SARS-CoV-2
  • Tetrahydroisoquinolines* / pharmacology

Substances

  • Heterocyclic Compounds
  • Tetrahydroisoquinolines
  • Chloroquine
  • Hydroxychloroquine
  • Antiviral Agents

Grants and funding

This research was funded by the National Natural Science Foundation of China (grant number: 82061138021); the Bulgarian National Science Fund (grant number: KP-06-DK3/1); Hubei Natural Science Foundation for Distinguished Young Scholar (grant number: 2021CFA050); Key Biosafety Science and Technology Program of Hubei Jiangxia Laboratory (grant number: JXBS001); Special Research Assistant Program of Chinese Academy of Sciences (grant number: 2021000038); Hubei Postdoctoral Innovation Research Position (grant number: 2020000127).