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Research Articles

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

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Pages 3213-3222 | Received 21 Jul 2020, Accepted 30 Oct 2020, Published online: 13 Nov 2020
 

Abstract

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

Communicated by Ramaswamy H. Sarma

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was supported by Coordenadoria de Aperfeiçoamento Pessoal de Nível Superior (CAPES, Brazil) and Instituto Carlos Chagas – FioCruz (ICC, Brazil).

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