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

A class of tetrahydropyrazino[2,1-a:5,4-a′]diisoquinoline\nderivatives were synthesized under environmentally friendly conditions\nusing water as the solvent. The 3-D structures of some synthesized\ncompounds were determined by X-ray diffraction. Since naturally occurring\nisoquinoline alkaloids have significant antiviral activities against\na wide range of viruses, including coronaviruses, the synthesized\ncompounds were assayed for their inhibitory activities against SARS-CoV-2.\nOur results showed that the active compounds <b>50</b> and <b>96</b> blocked the delta SARS-CoV-2 entry into VeroE6 cells to\ndisplay EC<sub>50</sub> of 26.5 ± 6.9 and 17.0 ± 3.7 μM,\nrespectively, by inhibiting the interaction between SARS-CoV-2 Spike’s\nreceptor binding domain (RBD) and human receptor angiotensin-converting\nenzyme 2 (ACE2), and CC<sub>50</sub> greater than 100 μM. This\nstudy provides a green synthesis method of tetrahydropyrazinodiisoquinoline\nfor antiviral or other applications.