Disrupting leishmania redox homeostasis: Mechanistic insights into a platinum-based antileishmanial complex

Leishmaniasis remains a major neglected tropical disease, and the development of new chemotherapeutic agents with improved selectivity and novel mechanisms is urgently required. Since the discovery of cisplatin, platinum-based compounds have been extensively developed for cancer therapy; however, their potential in the treatment of parasitic infections has received limited attention. Here, we report a mechanistic investigation of the antileishmanial activity of the platinum(II) complex [PtCl(phpy)(PTA)] , incorporating the oxidation-resistant phosphine ligand 1,3,5-triaza-7-phosphaadamantane. The complex exhibited low-micromolar activity against Leishmania (L.) amazonensis promastigotes and axenic amastigotes, with a favorable selectivity index relative to mammalian cells. Biological and biochemical analyses demonstrated that [PtCl(phpy)(PTA)] disrupts parasite mitochondrial bioenergetics, leading to impaired respiration, loss of mitochondrial membrane potential, and oxidative imbalance. In addition, the complex inhibited trypanothione reductase activity, a key enzyme in parasite redox homeostasis. This inhibition was accompanied by increased NADPH production via the pentose phosphate pathway, indicating a compensatory response to redox stress. Overall, these findings underscore the potential of platinum-based complexes to target redox and mitochondrial pathways in Leishmania , supporting metal-mediated redox disruption as a promising strategy for antileishmanial drug development. A phosphine-stabilized platinum(II) complex shows potent activity against L. amazonensis amastigotes with low toxicity to mammalian cells. The compound induces promastigote morphological alterations, inhibits trypanothione reductase, disrupts mitochondrial function, reduces oxygen consumption, and collapses membrane potential, ultimately leading to parasite death • A phosphine-stabilized platinum complex shows antileishmanial activity. • The complex impairs mitochondrial respiration and membrane potential. • Trypanothione reductase inhibition disrupts parasite redox balance. • Platinum compounds target redox and mitochondrial pathways in parasites.