M-8

In this study, we have selected a series of a new family of molecules bearing Triazolo-benzodiazepines, an eleven membered heterocyclic ring has been studied for antidepression activity. Docking studies suggested that all the eleven ligands interacted well within active site of Drosophila melanogaster dopamine transporter (dDAT) (PDB ID: 4M48). Most ligands formed H-bond with amino acid Phe43, Asp46, Asp475, Tyr123, Ser421 and/or Gln316 and also exhibited Pi and Pi-Pi interactions with amino acid residues Tyr124, Phe319, Phe43, Phe325, Ala479 and Val120. In silico ADME evaluations of compounds showed more than 96% intestinal absorption for all compounds. During in vitro Toxicity properties prediction, the Triazolo-benzodiazepines derivatives: M₁, M₂, M₃ and M₁₁ showed less toxicity than the other studied molecules against algae, for daphnia the molecules M₁, M₂, M₃, M₈, M₁₀ and M₁₁ showed less toxicity than the reference molecule (Nortriptyline).

In recent decades, some quinoxaline 1,4-di-N-oxide derivatives have been shown to have better trypanocidal activity than the reference drugs; however, their mechanism of action is not yet clear, although it is suggested that they mainly produce reactive oxygen species that cause oxidative stress and parasite death. Trypanosoma cruzi relies on the enzyme trypanothione reductase, among others, to defend itself against oxidative stress. With the aim of contributing to the elucidation of the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives on Trypanosoma cruzi, this study was carried out to evaluate the effect of methyl 2-amide-3-methylquinoxaline-7-carboxylate 1,4-di-N-oxide (compound M-8) on the expression of the trypanothione reductase gene in an in vitro model on Trypanosoma cruzi epimastigotes of the CL-Brener strain. The results show that compound M-8 does not cause a significant effect on the trypanothione reductase gene, suggesting a mechanism of action not related to oxidative stress.