Pt(II) and Pd(II) complexes with coumarin-thiosemicarbazone hybrid ligands and triphenylphosphine coligand as potential anti T. cruzi agents

Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. The disease is endemic in 21 Latin American countries, but it has also been found worldwide. Current treatments for Chagas disease are not effective in all stages of the disease and can have severe side effects. In recent years, there has been a growing interest in the development of new drugs for the treatment of Chagas disease, including metal complexes containing bioactive ligands. In this work, we designed and synthesized eight novel palladium and platinum complexes of the formula [M(L)(PPh3)] containing four different coumarin-thiosemicarbazone hybrid ligands (H2L) as bioactive ligands and triphenylphosphine as lipophilic co-ligand. Compounds were characterized in the solid state and in solution including the resolution of the crystal structure of two of them by single crystal X-ray diffraction. The activity of these hybrids and their corresponding complexes against T. cruzi, along with their unspecific cytotoxicity, was assessed. The results showed that the palladium complexes fairly improved the ligands´ anti-T. cruzi activity in vitro but also the cytotoxicity on some mammalian cell lines. The most active palladium compound decreased the rate of parasitic infection of Vero cells. Synergy studies with benznidazole were also performed for this compound. In addition, we explored mitochondrion disruption and ROS generation as potential modes of action for the obtained compounds. Further studies are needed to optimize the design of new compounds to attain less unspecific toxicity and higher anti T. cruzi activity.