Green Synthesis of Tetrahydropyrazino[2,1-a:5,4-a′]diisoquinolines as SARS-CoV-2 Entry Inhibitors

A class of tetrahydropyrazino[2,1-a:5,4-a']diisoquinoline derivatives were synthesized under environmentally friendly conditions using water as the solvent. The 3-D structures of some synthesized compounds were determined by X-ray diffraction. Since naturally occurring isoquinoline alkaloids have significant antiviral activities against a wide range of viruses, including coronaviruses, the synthesized compounds were assayed for their inhibitory activities against SARS-CoV-2. Our results showed that the active compounds <b>50</b> and <b>96</b> blocked the delta SARS-CoV-2 entry into VeroE6 cells to display EC₅₀ of 26.5 ± 6.9 and 17.0 ± 3.7 μM, respectively, by inhibiting the interaction between SARS-CoV-2 Spike's receptor binding domain (RBD) and human receptor angiotensin-converting enzyme 2 (ACE2), and CC₅₀ greater than 100 μM. This study provides a green synthesis method of tetrahydropyrazinodiisoquinoline for antiviral or other applications.