An evaluation of spirooxindoles as blocking agents of SARS-CoV-2 spike/ACE2 interaction : synthesis, biological evaluation and computational analysis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained significant public health attention owing to its devastating effects on lives and livelihoods worldwide. Due to difficult access to vaccines in many developing countries and the inefficiency of vaccines in providing complete protection even with fully vaccinated persons, there remains the need for the development of novel drugs to combat the disease. This study describes the in vitro activity of a library of fifty-five spiro-fused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) as potential blocking agents of the interaction between the SARS-CoV-2 viral spike and the human angiotensin-converting enzyme 2 (ACE2) receptor, essential for viral transmission. The synthesis was conducted by the Pictet-Spengler condensation of phenethylamine and isatin derivatives, while the screening against spike-ACE2 interaction was done using our previously described AlphaScreen fluorescent assay. The in vitro screening identified compound (11j) as the most active, showing a 50% inhibitory concentration (IC50) of 3.6 μM against SARS-CoV-2 spike/ACE2 interaction. Structure-activity relationships explained via molecular docking studies and the computation of binding free energy of each compound with respect to the spike/ACE2 protein-protein interaction showed that 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. Therefore, these compounds could be potentially useful in searching for SARS-CoV-2 spike/ACE2 interaction blocking agents.