Copper(II) benzyloxychalcone analogues as new potential metallodrugs against SARS-CoV-2 replication

Chalcones, a naturally occurring class of molecules found in various plants, serve as both precursors and final products in the biosynthesis of flavonoids. Renowned for their diverse therapeutic actions, chalcones demonstrate anti-inflammatory, antitumoral, antimalarial and antiviral activities. The structure of chalcones allows chemical manipulation, making them attractive for metal coordination, such as with copper, an essential metal for living organisms. Here, we characterize the activity of CuL₂phen and CuL₁phen against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in which L1 and L2 are two forms of the chalcones 3-(4-(benzyloxy)phenyl)-1-(4-fluoro-2-hydroxyphenyl)prop-2-en-1-one and 3-(4-(benzyloxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one, respectively, and phen is phenanthroline. CuL₁phen and CuL₂phen anti-SARS-CoV-2 activity were studied in the viral replication cycle employing both the SARS-CoV-2-NeonGreen infectious clone and wild-type isolates. The SI of CuL₁phen and CuL₂phen was found to be 1.7 and 5.5, respectively, demonstrating that CuL₂phen is a more promising compound. CuL₂phen impaired SARS-CoV-2 entry, predicted by molecular docking calculations to disrupt the glycoprotein S and angiotensin-converting enzyme 2 (ACE2) binding, emphasized by the low EC₅₀ in pseudotyped virus entry assay. Further, CuL₂phen was identified as SARS-CoV-2 post-entry inhibitor, probably due to its strong interaction with SARS-CoV-2 double stranded RNA. Altogether, the data suggest that CuL₂phen acts by impairing SARS-CoV-2 entry by disrupting the viral envelope as well as interrupting RNA replication through specifically intercalating into the dsRNA. The obtained results give us mechanistic insights into the activity of this promising Cu(II) metallodrug candidate in SARS-CoV-2 infection.