期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 40, 期 7, 页码 3213-3222出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1845979
关键词
Thiohydantoins; heterocyclic; molecular consensual docking; arginase; trypanothione reductase; L; amazonensis
资金
- Coordenadoria de Aperfeicoamento Pessoal de Nivel Superior (CAPES, Brazil)
- Instituto Carlos Chagas FioCruz (ICC, Brazil)
Leishmaniasis is a neglected tropical disease with limited treatment options. Thiohydantoins, a class of substances, show promising anti-leishmanial activity against the parasite in vitro and low cytotoxicity to human cells. These compounds induce oxidative stress and a late apoptosis-like process in the parasites. Molecular docking analysis suggests that the thiohydantoin ring may serve as a pharmacophoric group.
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 1a-l were evaluated in vitro for antileishmania activity. Among them, four derivatives (1c, 1e, 1h and 1l) showed promising IC50 values around 10 mu M 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
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