Design, synthesis and biological evaluation of new copper complexes functionalized with the antiviral agent amantadine

Copper(I) and copper(II) complexes have received great attention for their both in vitro and in vivo unique properties. We have recently reported a library of Cu complexes with heteroscorpionate ligands, obtained via conjugation with nitroimidazole, glucosamine, a noncompetitive NMDA receptor antagonist and the antineoplastic drug lonidamine, showing cytotoxic activity toward a panel of human tumor cell lines. Here we report Cu(I) and Cu(II) complexes functionalized with the antiviral agent amantadine. The bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetic acids were selected as bifunctionalizable coordinating agents for the synthesis of the ligands due to the k3-NNO coordination behavior of bis(azol-1-yl)acetates and to the presence of a carboxylic function suitable for the coupling with primary amine groups. Phosphane co-ligands, such as the lipophilic PPh3 and the hydrophilic PTA, were selected for the synthesis of the new Cu(I) complexes to stabilize copper in +1 oxidation state and confer different solubility properties to the corresponding complexes. All the newly synthesized complexes were primarily evaluated for their cytotoxicity on two mammalian immortalized cell lines, such as HaCaT and Vero E6 cells, by MTT cell viability assay. The results highlighted that all the Cu(II) complexes and the Cu(I)-PTA complexes showed good biocompatibility profiles at both the studied cell lines and have been selected to be tested in vitro for their antiviral activity by using lentiviral vectors expressing luciferase in Vero E6 cells. The most performing species will be also spin-coated or electro-sprayed on different substrates and the antiviral efficacy of the deposits will be evaluated to test the feasibility of Cu-functionalized surfaces.