Mn(III) Porphyrin MnTE-2-PyP⁵⁺ Associated with Ascorbate: A Redox-Active Therapeutic Strategy against Leishmaniasis

Toxicity and rising resistance to current leishmaniasis drugs highlight the need for alternative therapies. Manganese porphyrins (MnPs) have demonstrated therapeutic potential in various oxidative stress-based diseases/ailments due to their redox-modulating properties. Thus, this study aimed to evaluate the redox-active effects of MnTE-2-PyP⁵⁺ (BMX-010, AEOL10113, MnP ethyl) combined with ascorbate (Asc, vitamin C) on Leishmania amazonensis, Leishmania braziliensis, and Leishmania chagasi in vitro. The effects on promastigote growth were assessed, and the mechanism of action was studied by quantifying reactive oxygen species (ROS) and using catalase to evaluate H₂O₂ involvement. The effects on intracellular amastigotes and the mitochondrial membrane potential (ΔΨm) of promastigotes from the most susceptible species were evaluated. Cytotoxicity assays were carried out on mammalian cells. MnP ethyl alone had no impact on parasite growth; however, MnP ethyl/Asc treatment led to a significant reduction in the promastigote growth: 88% for L. amazonensis, 43% for L. chagasi, and 37% for L. braziliensis after 48 h. MnP ethyl/Asc generated about 300% more ROS than the untreated control and induced ΔΨm depolarization. Catalase addition restored parasite survival, confirming H₂O₂ as the primary mediator of the MnP ethyl/Asc effect. Moreover, MnP ethyl/Asc exhibited minimal cytotoxicity on mammalian cells. The MnP ethyl/Asc treatment reduced the infection index by about 58% and the number of amastigotes per macrophage by 42% in L. amazonensis after 24 h. These findings demonstrated that MnP ethyl/Asc exerted an antileishmanial effect through oxidative stress, providing a promising alternative for preclinical evaluation.