Quinoline-Aminothiophenol Derivative Triggers Pronounced Mitochondrial Dysfunction and Cell Death in Leishmania...

Current therapies for visceral leishmaniasis (VL) remain limited, underscoring the need for new therapeutic alternatives. Here, we investigated the activity of a novel quinoline analogue containing 2-aminothiophenol, designated TQCl, against Leishmania infantum and sought to provide initial insights into its mode of action. TQCl exhibited potent antileishmanial activity against promastigotes and intracellular amastigotes, with IC₅₀ values below 10 μM and a selectivity index greater than 10. In silico consensus docking suggested Trypanothione Reductase (LiTryR) as a potential molecular target, with a predicted binding affinity (cKi = 3.6 μM) for the closed resting state (S1_closed). The compound induced pronounced morphological, ultrastructural, and biochemical alterations in promastigote forms. Time-course analysis showed that TQCl triggers rapid mitochondrial depolarization within 3-6 h. This precedes and is chronologically associated with a late-stage burst of total ROS and superoxide at 24 h, lipid droplet accumulation, and plasma membrane permeabilization, as mapped by multidimensional spider plots. TQCl also disrupted the parasite cell cycle, leading to abnormal flagellar phenotypes and extensive cytoplasmic vacuolation. In infected macrophages, TQCl increased NO production without altering ROS levels, with a strong linear correlation (R2 = 0.9894) between NO levels and the reduction in intracellular parasite burden. Collectively, the results indicate that TQCl induces multiple parasite and host-associated phenotypic effects, including apoptosis-like and necrosis-related features and an NO-associated microbicidal response. Preliminary in silico ADMET profiling indicates encouraging pharmacokinetic trends, providing initial theoretical support for future in vivo evaluation in murine VL models.