Exploring Metal-Based Compounds as Antiviral Agents Targeting the SARS- CoV-2 Main Protease

The SARS-CoV-2 main protease (MPro) is an important molecular target for antiviral drug development. Based on the inhibitory activity previously reported for thiosemicarbazones and their metal complexes against cysteine proteases, a series of Pd(II) and Pt(II) complexes were synthesized and characterized. The influence of chloride and triphenylphosphine (PPh3) co-ligands on biological activity was evaluated. Free thiosemicarbazones showed low to moderate MPro inhibition (IC50 >= 10-20 uM). Metal complexation strongly affected the inhibitory properties depending on the co-ligand. Complexes containing PPh3 displayed reduced activity, whereas chloride-containing complexes exhibited enhanced inhibition, with IC50 values ranging from 0.3 to 15 uM and up to an 80-fold increase compared with the free ligands. Molecular docking suggested that PPh3 may hinder interaction with Cys145 at the catalytic site. Among the evaluated compounds, [PtCl(HL4)] showed the most promising antiviral profile, with an EC50 of 1.8 uM and a selectivity index of 8.4.