Antiparasitary and antiproliferative activities in vitro of a 1,2,4-oxadiazole derivative on Trypanosoma cruzi.
Yasmim Mendes RochaEmanuel Paula MagalhãesMarlos de Medeiros ChavesMárcia Machado MarinhoValentina Nascimento E Melo de OliveiraRonaldo Nascimento de OliveiraTiago Lima SampaioRamon R P P B de MenezesAlice M C MartinsRoberto NicoletePublished in: Parasitology research (2022)
Chagas disease (CD) is a neglected disease, prevalent and endemic in Latin America, but also present in Europe and North America. The main treatment used for this disease is benznidazole, but its efficacy is variable in the chronic phase and presents high toxicity. So, there is a need for the development of new therapeutic agents. The five-membered heterocyclic 1,2,4-oxadiazole ring has received attention for its unique properties and a broad spectrum of biological activities and is therefore a potential candidate for the development of new drugs. Thus, the aim of this study was to evaluate the activity of the N-cyclohexyl-3-(3-methylphenyl)-1,2,4-oxadiazol-5-amine (2) on the evolutionary forms of Trypanosoma cruzi strain Y, as well as its mechanisms of action and in silico theoretical approach. The results by computational method showed an interaction of the 1,2,4-oxadiazole (2) with TcGAPDH, cruzain, and trypanothione reductase, showing good charge distribution and affinity in those three targets. Furthermore, cytotoxicity in LLC-MK 2 cells was performed by the MTT method. In the assays with different parasite forms, the tested compound showed similar time-dependent concentration effect. The evaluation of the antiamastigote effect between the two concentrations tested showed a reduction in the number of infected cells and also in the number of amastigotes per infected cell. By flow cytometry, the compound (2) displayed alterations suggestive of necrotic events. Finally, in scanning electron microscopy structural alterations were present, characteristic of necrosisin the epimastigote forms. Overall, the 1,2,4-oxadiazole derivative (2) here evaluated opens perspectives to the development of new antichagasic agents.
Keyphrases
- trypanosoma cruzi
- induced apoptosis
- electron microscopy
- flow cytometry
- cell cycle arrest
- oxidative stress
- single cell
- signaling pathway
- high resolution
- gene expression
- endoplasmic reticulum stress
- cell death
- dna methylation
- cell therapy
- molecular docking
- risk assessment
- mass spectrometry
- combination therapy
- molecular dynamics simulations