Novel biocompatible copper complexes potentially useful as antiviral agents

Copper complexes have gained great interest over the years for their versatile applications in medicinal inorganic chemistry. We have recently reported Cu(I) and Cu(II) complexes with heteroscorpionate ligands conjugated with different biomolecules, including a noncompetitive NMDA receptor antagonist and the anticancer drug lonidamine, endowed with cytotoxic activity toward a panel of human tumor cell lines. Here we describe the synthesis and biological evaluation of new Cu(I) and Cu(II) complexes functionalized with the antiviral agent amantadine (Figure). The bis(pyrazol-1-yl)acetic acid LH was selected as a bifunctionalizable coordinating agent for the preparation of the ligand LCS7 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 the primary amine group of amantadine. For the synthesis of the novel Cu(I) complexes, phosphane co-ligands, such as the hydrophilic PTA and the lipophilic PPh3, were selected to stabilize copper in +1 oxidation state and to confer different solubility properties to the corresponding complexes. All the newly synthesized complexes were primarily evaluated by MTT cell viability assay for their cytotoxicity on two mammalian immortalized cell lines, such as HaCaT and Vero E6 cells, and the most biocompatible ones were selected to be tested for their in vitro antiviral activity by using lentiviral vectors expressing luciferase in Vero E6 cells.