Comparative Study of the Anti-trypanosomatid Activity of Pd(II) and Pt(II) Complexes with Coumarin-Thiosemicarbazone Derivatives

To develop novel anti-trypanosomatid agents, we synthesized two families of coumarin-thiosemicarbazone ligands and their [M(L)(PPh3)] (M = Pd, Pt) complexes. The first family (L1-L4), lacking substituents on the coumarin moiety, exhibited limited activity against Trypanosoma cruzi. To enhance efficacy, a second family (L5-L8) was designed incorporating a nitro group, inspired by the drug Nifurtimox. This structural modification remarkably improved the anti-T. cruzi activity of the ligands and metal complexes. Furthermore, screening against Trypanosoma brucei brucei revealed that the nitro-containing derivatives display significantly higher activities and selectivities, achieving sub-micromolar IC50 values and selectivity indexes up to 230. This comparative study highlights the critical role of nitro group inclusion in improving the efficacy and selectivity of coumarin-thiosemicarbazone complexes. Currently, these promising nitro-containing Pd(II) and Pt(II) complexes are under further biological evaluation to fully assess their potential against trypanosomatid parasites.