1,10-phenanthroline enhances the antiparasitic activity and selectivity of Cu(II) and Zn(II) metal complexes with coumarin-thiosemicarbazone hybrid ligands

Chagas disease, caused by Trypanosoma cruzi, remains a major public health concern with limited therapeutic options and significant toxicity associated with current treatments. In this work, eight novel heteroleptic complexes of the type [M(L)(phen)], where M = Cu(II) or Zn(II), L = coumarin-thiosemicarbazone hybrid ligands, and phen = 1,10-phenanthroline, were synthesized and fully characterized in the solid state and in solution. For comparison, some homoleptic [Cu(HL)₂], [Zn(HL)₂], and [CuCl(HL)] complexes were also prepared. All compounds were evaluated in vitro against Trypanosoma cruzi trypomastigotes. The presence of the phenanthroline co-ligand markedly enhanced trypanocidal activity in both metal series. The [Cu(L)(phen)] complexes showed the highest potency, with submicromolar half-maximal inhibitory concentration values and favourable selectivity indexes. Mechanistic studies revealed that these copper complexes increased intracellular reactive oxygen species and caused mitochondrial membrane depolarization, leading to necrosis as the primary mechanism of parasite death. The redox-active nature of copper likely contributes to this enhanced activity. These findings underscore the relevance of phenanthroline in modulating antiparasitic efficacy and support further development of copper-based complexes bearing this ligand as potential agents for Chagas disease treatment.