An evaluation of spirooxindoles as blocking agents of SARS-CoV-2 spike/ACE2 fusion and M pro inhibitory agents: Synthesis, biological evaluation and computational analysis

Abstract

Both tetrahydroisoquinolines (THIQs) and oxindoles (OXs) display a broad range of biological activities, including antiviral activity. They are, therefore, recognized as privileged scaffolds in drug discovery. Here, we describe the synthesis of spirofused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) and their evaluation as potential blocking agents of both SARS-CoV-2 spike/ACE fusion and inhibitors of the main protease (M^pro). The most active synthesized compound showed a 50% inhibitory concentration (IC₅₀) of 3.6 µM against SARS-CoV-2 spike/ACE fusion. None of the tested compounds was shown to be active against M^pro. The most active compound possesses a bulky naphthyl group, which addresses voluminous hydrophobic regions of the ACE2 binding site and interacts with the hydrophobic residues of the target; this finding agrees with previous studies revealing that bulky compounds block spike/ACE2 fusion, e.g., the natural product hopeaphenol. Therefore, spirooxindoles may provide useful leads in the search for SARS-CoV-2 spike/ACE fusion blocking agents.