Design, synthesis, and biological and computational evaluation of novel oxindole derivatives as inhibitors of Aurora A Kinase and SARS-CoV-2 Spike/Host ACE2 Interaction

Abstract

Abstract Isatin (indol-2,3-dione), a secondary metabolite of tryptophan has been used as the core structure in the designation of several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogues of isatin hybrids have been synthesized and characterized, and their inhibitory activities established as inhibitors of both Aurora A kinase and SARS-CoV-2 spike/host ACE2 interactions. Amongst the synthesized isatin hybrids, compounds 6a – 6d, and 6m exhibited interesting Aurora A kinase inhibitory activity while compounds 6h and 6l showed interesting activity in blocking SARS-CoV-2 spike with the ACE2 protein. Compounds 6f, 6g, and 6i possessed both inhibitory activities. Pharmacophore profiling indicated that compound 6g, tightly fits Aurora A kinase and SARS-CoV-2 pharmacophore while 6d fits SARS-CoV-2 and 6l Aurora A kinase. This work is a proof of concept that most existing cancer drugs possess antiviral properties. Molecular modeling showed that the active compound for each protein adopted different binding modes, hence interacting with a different set of amino acid residues in the binding site. For the Aurora A kinase inhibitors, it was shown that the important residues for binding were Leu139, Ala213, Lys162 and Glu211. The weaker activities against spike/ACE2 could be explained by the small sizes of the ligands that fail to address the important interactions for binding to the angiotensin II receptor site.