Mitochondrial Dysfunction Induced by a Novel Salicylate‐Based 1,2,3‐Triazole Salt With Potent Antileishmanial Activity

Leishmaniasis is a neglected disease caused by Leishmania spp., with limited treatment options and no available vaccine. In this study, novel 1,2,3-triazole derivatives 4-substituted with salicylic esters and their salts were synthesized and evaluated against L. amazonensis. While neutral compounds were inactive, their salts effectively inhibited both promastigote and intracellular amastigote growth. Compound 7 exhibited the highest antileishmanial activity and selectivity (IC₅₀ against amastigotes of 6.23 ± 0.35 μM; SI of 17.81), surpassing miltefosine, the positive control. Additionally, this compound exhibited no hemolytic effect. Studies further demonstrated that at early time points (6 h), treatment with compound 7 led to a marked increase in total ROS and mitochondrial superoxide levels, although no change in mitochondrial membrane potential was detected, indicating an initial oxidative imbalance without immediate effects on ΔΨm. However, after 24 h of treatment, this sustained oxidative stress resulted in pronounced mitochondrial membrane potential hyperpolarization, while elevated ROS levels persisted. Throughout these assays, plasma membrane integrity remained unaffected in treated L. amazonensis promastigotes. In silico analyses suggested favorable pharmacokinetic properties and oral bioavailability. Collectively, these findings highlight compound 7 as a promising candidate for further studies, including in vivo assays using murine models of leishmaniasis.