Estudo da atividade antileishmanial e do modo de ação de um derivado de quinolina-aminotiazol em Leishmania infantum, responsável pela leishmaniose visceral americana

Abstract

Visceral leishmaniasis (VL) is caused by protozoa of the Leishmania donovani complex, with L. infantum being widely distributed worldwide and responsible for zoonotic transmission in the Americas, where the domestic dog acts as the main reservoir in urban environments. Additionally, it is classified among the so-called “Neglected Tropical Diseases” by the World Health Organization. VL represents a One Health issue, as it interconnects human, animal, and environmental health. Current therapies for VL remain limited due to prolonged treatment regimens, parenteral administration, and significant toxic effects, as well as therapeutic failure, drug resistance, and relapses, highlighting the need for research into new therapeutic alternatives for both humans and dogs. Thus, this study aimed to investigate the activity and selectivity of a novel quinoline analog containing 2-aminothiophenol, named TQCL, against L. infantum, as well as to provide insights into its mechanism of action. After 72 hours of treatment with TQCL, activity in promastigotes and toxicity in mammalian cells were assessed using the MTT assay, while intracellular amastigotes were evaluated by counting the parasite load in L. infantum infected peritoneal macrophages following Giemsa staining. For mechanistic studies in treated promastigotes, specific fluorescent probes and transmission and scanning electron microscopy approaches were employed. TQCL exhibited potent antileishmanial activity against promastigotes and intracellular amastigotes, with CI₅₀ values below 10 μM and a selectivity index greater than 10 in promastigotes, TQCL induced pronounced morphological, ultrastructural, and biochemical alterations, with mitochondrial dysfunction as a central event, followed by changes consistent with apoptosis, paraptosis, and necrosis-like cell death. Treatment of infected macrophages induced an increase in NO production, suggesting a potential stimulation of the microbicidal activity of macrophages. Taken together, the results indicate that TQCL inhibits the growth of L. infantum through multiple mechanisms, revealing a crucial strategy of coordinated dysregulation of vital cellular processes in the in vitro model, and opening perspectives for its evaluation in experimental visceral leishmaniasis.