Thiohydantoins as anti-leishmanial agents: <i>n vitro</i> biological evaluation and multi-target investigation by molecular docking studies

Abstract

Leishmaniasis is a neglected tropical disease caused by protozoa of the genus <i>Leishmania</i>. 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 <b>1a</b>-<b>l</b> were evaluated <i>in vitro</i> for antileishmania activity. Among them, four derivatives (<b>1c</b>, <b>1e</b>, <b>1h</b> and <b>1l</b>) showed promising IC₅₀ values around 10 µM against promastigotes forms of <i>Leishmania amazonensis</i> 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 <i>L. amazonensis</i>: 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 <b>1c</b>, <b>1e</b>, <b>1h</b> and <b>1l</b> may are promising in future advance studies.Communicated by Ramaswamy H. Sarma.