Gustavo Clauss Rodrigues

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 CuL ₂ phen and CuL ₁ phen 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. CuL ₁ phen and CuL ₂ phen 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 CuL ₁ phen and CuL ₂ phen was found to be 1.7 and 5.5, respectively, demonstrating that CuL ₂ phen is a more promising compound. CuL ₂ phen 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 EC ₅₀ in pseudotyped virus entry assay. Further, CuL ₂ phen 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 CuL ₂ phen 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.

This study employed semiempirical GFN-xTB and density functional theory (DFT) calculations to investigate ligand exchange reactions of linear complexes [M(NHC)Cl] (M = Au(I) or Cu(I), NHC = N-heterocyclic carbenes) relevant to medicinal chemistry. Despite their potent in vitro antitumor, antibacterial, and antiparasitic activities, speciation limits their application. The research explored three biologically relevant reactions. Firstly, chloride substitution with dimethylsulfoxide (DMSO), the solvent used to prepare stock solutions before in vitro studies. Secondly, ligand scrambling involves the rearrangement of ligands in solution forming [M(NHC)2][MCl2]. Lastly, chloride substitution with cysteine, a biologically relevant ionic amino acid. Thermodynamically and kinetically, chloride replacement by DMSO is less favorable than ligand scrambling, particularly for Cu(I) complexes, suggesting [M(NHC)Cl] is the most abundant species present followed by [M(NHC)2][MCl2], the last mainly in Cu(I) complexes. Cysteine substitution proves to be the most thermodynamically and kinetically favorable, potentially impacting the biological mechanism of action. The study also compares reaction mechanisms between Au(I) and Cu(I) complexes by analyzing transition state geometries. This research enhances understanding of ligand exchange reactions in linear complexes, shedding light on thermodynamic and kinetic preferences and biological mechanisms. The insights from the current work aid the interpretation of in vitro and in vivo data, unlocking the potential of these complexes for medicinal applications.