Thiohydantoins as anti-leishmanial agents: biological evaluation and multi-target investigation by molecular docking studies.

Leishmaniasis is a neglected tropical disease caused by protozoa of the genus . The first-line treatment of this disease is still based on pentavalent antimonial drugs that have a high toxicity profile, which could induce parasitic resistance. Therefore, there is a critical need to discover more effective and selective novel anti-leishmanial agents. In this context, thiohydantoins are a versatile class of substances due to their simple synthesis and several biological activities. In this work, thiohydantoins - were evaluated for antileishmania activity. Among them, four derivatives (, , and ) showed promising IC values around 10 µM against promastigotes forms of and low cytotoxicity profile for peritoneal macrophages cells. Besides, these compounds induce oxidative stress through an increase in ROS production and the labeling of annexin-V and propidium iodide, indicating that promastigotes were undergoing a late apoptosis-like process. Additionally, molecular consensual docking analysis was carried out against two important targets to : arginase and trypanothione reductase enzymes. Docking results suggest that thiohydantoin ring could be a pharmacophoric group due to its binding affinity by hydrogens bond interactions with important amino acid residues at the active site of both enzymes. These results demonstrate that compounds , , and may are promising in future advance studies.Communicated by Ramaswamy H. Sarma.