Dados do Trabalho

Título

Activity of a 2-Aminobenzimidazole Derivative on Leishmania infantum as a Trypanothione Reductase Inhibitor: Insights into ROS Induction Pathways

Introdução

Leishmaniases are neglected tropical diseases, affecting more than 1 billion people living in endemic areas which are at risk of infection. It is estimated that more than 1 million new cases of cutaneous leishmaniasis occur annually, and 30,000 new cases of visceral leishmaniasis, also known as kala-azar, which is fatal in over 95% of cases if left untreated. The treatment for these diseases had very few innovations in over 80 years and the current medicines have therapeutic limitations, including drug resistance, toxicity, and high costs. Therefore, there is an urgent need for new chemotherapeutic agents that are more effective and have fewer adverse effects. In this context, the discovery of new compounds as well as the search for targets that can be explored in the development of new anti-Leishmania drugs is of utmost importance.

Objetivo (s)

Therefore, this study aims to investigate the in vitro anti-Leishmania action of a new compound, 2-aminobenzimidazole (6T-BDC), and conduct pharmacokinetic and molecular docking studies to assess its drug-like properties and binding interaction pattern with the enzyme trypanothione reductase (TryR), a potential target for drug development. 

Material e Métodos

The cytotoxicity (CC50) of 6T-BDC in primary peritoneal mouse macrophages (PMM) and its effectiveness against intracellular amastigote forms of Leishmania infantum were evaluated. Molecular modeling studies explored the interactions between 6T-BDC and the TryR enzyme (PDB ID 2JK6, 2.95 Å). Additionally, in silico prediction studies (pkCSM and SwissADME) on physicochemical and pharmacokinetic properties were conducted. 

Resultados e Conclusão

Results indicate that 6T-BDC, with IC50 value of 2.2 µM, exhibits comparable activity to miltefosine (IC50 value of 2.52 µM) against L. infantum. Cytotoxicity testing of 6T-BDC in PMM cells indicated a promising selectivity of over 10-fold. Analysis of the LUMO orbital highlights a specific aromatic segment, suggesting a potential mechanism for generating reactive oxygen species (ROS). Molecular modeling revealed relevant interactions with key residues of TryR. In silico evaluations, based on the criteria of Lipinski, Ghose, Veber, Egan, and Muegge, highlight the potential of 6T-BDC as a lead compound for developing new antiparasitic agents for leishmaniasis therapy. Our findings suggest that 6T-BDC warrants comprehensive investigation, offering valuable insights into the medicinal chemistry of anti-Leishmania agents and the potential of TryR as a therapeutic target.  

Palavras Chave

Leishmania infantum; 2-aminobenzimidazole; trypanothione reductase; computational studies.