Fernanda Ramos Gadelha

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 . AuPPh ₃ Cl and AuPPh ₃ MTZ showed potent activity against promastigote and axenic amastigotes, with low micromolar EC ₅₀ 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. AuPPh ₃ Cl induced higher hydrogen peroxide levels than AuPPh ₃ MTZ , 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, AuPPh ₃ Cl 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.

Chagas disease (CD) is a parasitic infection caused by the protozoan Trypanosoma cruzi . CD treatment is restricted to benznidazole (BZN) and nifurtimox, with the former being the treatment of choice in many countries. Unfortunately, BZN demonstrates limited efficacy in the chronic phase of CD and leads to several side effects that often result in patients discontinuing the treatment. The emergence of BZN-resistant T. cruzi strains is also a major concern. Metal compounds have gained importance due to their unique physicochemical properties. Therefore, we conducted a 5-year systematic review, analysing 22 articles with the aim of compiling the results of the anti-trypanocidal effect of 113 compounds. Our results show that the majority of the compounds centre on Cu (17%), followed by Zn (12%) and Sn (9%). Most exhibit an anti- T. cruzi effect across all life-cycle forms, with epimastigotes generally being more resistant than trypomastigotes. Only 43 compounds (38%) had their mode of action elucidated, which included disruption of mitochondrial membrane potential, an increase in reactive oxygen species generation, and inhibition of ergosterol synthesis, cruzain, trypanothione reductase, and fumarate reductase. Despite our inability to establish the most effective metal compound due to a lack of standardisation in the methods used, this review seeks to outline a path for the design of new metallodrugs, a class of compounds that warrants further investigation for its promising anti- T. cruzi activity.

Leishmaniasis is a worldwide disease caused by more than 20 species of Leishmania parasites. Leishmania amazonensis and L. braziliensis are among the main causative agents of cutaneous leishmaniasis, presenting a broad spectrum of clinical forms. As these pathologies lead to unsatisfactory treatment outcomes, the discovery of alternative chemotherapeutic options is urgently required. In this investigation, a leishmanicidal bioassay-guided fractionation of the growth media extract produced by Aspergillus terreus P63 led to the isolation of the cyclic depsipeptide beauvericin (1). The viability of L. amazonensis, L. braziliensis and mammalian cells (macrophages and L929 fibroblasts) was assessed in 1 incubated cultures. Leishmania promastigotes were sensitive to 1, with EC₅₀ values ranging from 0.7 to 1.3 μM. Microscopy analysis indicated that Leishmania spp. parasites showed morphological abnormalities in a dose-dependent manner in the presence of 1. L. amazonensis intracellular amastigotes were more sensitive to 1 than promastigotes (EC₅₀ = 0.8 ± 0.1 μM), with a good selectivity index (22-30). 1 reduced the infectivity index at very low concentrations, maintaining the integrity of the primary murine host cell for up to the highest concentration tested for 1. In vivo assays of 1 conducted using BALB/c mice infected with stationary-phase promastigotes of L. amazonensis in the tail base presented a significant reduction in the lesion parasite load. A second round of in vivo assays was performed to assess the efficacy of the topical use of 1. The results demonstrated a significant decrease in the total ulcerated area of mice treated with 1 when compared with untreated animals. Our results present promising in vitro and in vivo leishmanicidal effects of beauvericin, emphasizing that systemic inoculation of 1 led to a decrease in the parasite load at the lesion site, whereas topical administration of 1 delayed the progression of leishmaniasis ulcers, a cure criterion established for cutaneous leishmaniasis management.