Synthesis of cannabidiol-based compounds as ACE2 inhibitors with potential application in the treatment of COVID-19

Cannabis is a general name for plants of the genus Cannabis. Used as fiber, medicine, drug, for religious, therapeutic, and hedonistic purposes along the millenia, it is mostly known for its psychoactive properties. One of its major constituents, cannabidiol (CBD), a non-psychoactive substance, among many other biological activities, has shown potential as an anti-SARS-CoV-2 drug. In this work, three derivatives and an analogue of CBD were synthesized, and cell viability and antiviral activities were evaluated. None of the compounds showed cytotoxicity up to a maximum concentration of 100 μM and, in contrast, displayed a significant antiviral activity, superior to remdesivir and nafamostat mesylate, with IC₅₀ values ranging from 9.4 to 1.9 μM. In order to search for a possible molecular target, the inhibitory activity of the compounds against ACE2 was investigated, with expressive results (IC₅₀ ranging from 3.96 μM to 0.01 μM).