SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic, in which acute respiratory infections are associated with high socio-economic burden. We applied target based and high-content screening approach to a well-defined collection of 5632 compounds including 3488 that have undergone previous clinical investigations across 600 indications. In phenotypic assays,  compounds were screened by microscopy for their ability to inhibit SARS-CoV-2 cytopathicity in the human epithelial colorectal adenocarcinoma cell line, Caco-2. The primary screen identified 258 hits that inhibited cytopathicity by more than 75%, most of which were not previously known to be active against SARS-CoV-2 in vitro.  The high-content screening data are suitable for reanalysis across numerous drug classes and indications and may yield additional insights into SARS-CoV-2 mechanisms and potential therapeutic strategies. Target based screens were run against key viral targets including the main (M) and papain like (PL) proteases and structural biology approches used to conform the MoA