Antileishmanial activity of gold(I) compounds containing triphenylphosphine ligands against Leishmania amazonensis: impacts on mitochondrial bioenergetics and trypanothione reductase activity.

Leishmaniasis poses a significant public health challenge, highlighting the urgent need for safer and more effective therapies. Here, we investigated the antileishmanial activity and mechanism of action of gold(I)-triphenylphosphine complexes against Leishmania amazonensis. AuPPh3Cl and AuPPh3MTZ showed potent activity against promastigote and axenic amastigotes, with low micromolar EC50 and favorable selectivity toward mammalian cells. Both compounds reduced infection rate and parasite burden in infected macrophages. Mechanistically, the complexes targeted mitochondrial function, resulting in increased oxygen consumption associated with dissipation of the mitochondrial membrane potential, without affecting respiratory coupling. These findings were accompanied by increased mitochondrial superoxide production, indicating a pro-oxidant effect. AuPPh3Cl induced higher hydrogen peroxide levels than AuPPh3MTZ, suggesting ligand-dependent differences in redox modulation. In addition, treated parasites displayed elevated NADPH levels, consistent with the activation of compensatory antioxidant responses. Both compounds inhibited trypanothione reductase activity in parasite extracts and with the purified enzyme. Notably, AuPPh3Cl showed greater selectivity toward the parasite enzyme over human glutathione reductase. Overall, these findings support a multitarget mechanism involving mitochondrial dysfunction and disruption of the trypanothione-dependent redox system, leading to oxidative imbalance and parasite death. Gold(I)-triphenylphosphine complexes represent promising candidates for the development of novel antileishmanial agents.