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Using a repurposing approach, a series of previously reported antiproliferative indole-based carboxamides (9 – 23) were reassessed for their anti-SARS-CoV-2 viral activity as main protease (SARS-CoV-2 Mpro) inhibitors. The structure of the indole-based carboxamides was validated by comparing the acquired data to previously report physicochemical and NMR spectroscopy data. The anti-SARS-CoV-2 activity of the synthesised compounds was tested in Vero-E6 cells using SARS-CoV-2 (NRC-03-nhCoV) virus. MTT cytotoxicity assay results demonstrated that compounds 9–23 had CC 50 (50% cytotoxicity concentration) values ranging from 325.60 to 578.50 μM and safety indices ranging from 21.40 to 99.60. Most of the compounds examined significantly inhibited NRC-03-nhCoV virus replication, with IC 50 values ranging from 3.60 μM to 15.20 μM, with compounds 11 , 19 , and 20 having the most potent anti-SARS-COV-2 activity. The inhibitory effect of compounds 11, 13, 14, 19 and 20 against SARS-CoV-2 Mpro was investigated. The findings of this test were consistent with the anti-SARS CoV-2 experiment. Inflammatory cytokine tests revealed that compounds 11 , 19 and 20 have antiviral effectiveness against SARS-CoV-2 and can reduce hyper inflammation. Finally, docking studies of the novel compounds in the SARS CoV-2-Mpro active site revealed a good match. [Display omitted] [ABSTRACT FROM AUTHOR]