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Context: Quinoxaline 1,4-di-N-oxide is a scaffold with a wide array of biological activities, particularly its use to develop new antiparasitic agents. Recently, these compounds have been described as trypanothione reductase (TR), triosephosphate isomerase (TIM), and cathepsin-L (CatL) inhibitors from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica, respectively. Methods: Therefore, the main objective of this work was to analyze quinoxaline 1,4-di-N-oxide derivatives of two databases (ZINC15 and PubChem) and literature by molecular docking, dynamic simulation and complemented by MMPBSA, and contact analysis of molecular dynamics' trajectory on the active site of the enzymes to know their potential effect inhibitory. Interestingly, compounds Lit_C777 and Zn_C38 show preference as potential TcTR inhibitors over HsGR, with favorable energy contributions from residues including Pro398 and Leu399 from Z-site, Glu467 from γ-Glu site, and His461, part of the catalytic triad. Compound Lit_C208 shows potential selective inhibition against TvTIM over HsTIM, with favorable energy contributions toward TvTIM catalytic dyad, but away from HsTIM catalytic dyad. Compound Lit_C388 was most stable in FhCatL with a higher calculated binding energy by MMPBSA analysis than HsCatL, though not interacting with catalytic dyad, holding favorable energy contribution from residues oriented at FhCatL catalytic dyad. Therefore, these kinds of compounds are good candidates to continue researching and confirming their activity through in vitro studies as new selective antiparasitic agents. [ABSTRACT FROM AUTHOR]

The development of new, more selective, environmental-friendly insecticide alternatives is in high demand for the control of Spodoptera frugiperda (S. frugiperda). The major objective of this work was to search for new potential S. frugiperda acetylcholinesterase (AChE) inhibitors. A ligand-based virtual screening was initially carried out considering six scaffolds derived from eugenol and the ZINC15, PubChem, and MolPort databases. Subsequently, molecular docking analysis of the selected compounds on the active site and a second region (determined by blind molecular docking) of the AChE of S. frugiperda was performed. Molecular dynamics and Molecular Mechanics Poisson–Boltzmann Surface Area analyses were also applied to improve the docking results. Finally, three new eugenol analogs were evaluated in vitro against S. frugiperda larvae. The virtual screening identified 1609 compounds from the chemical libraries. Control compounds were selected from the interaction fingerprint by molecular docking. Only three new eugenol analogs (1, 3, and 4) were stable at 50 ns by molecular dynamics. Compounds 1 and 4 had the best biological activity by diet (LC50 = 0.042 mg/mL) and by topical route (LC50 = 0.027 mg/mL), respectively. At least three new eugenol derivatives possessed good-to-excellent insecticidal activity against S. frugiperda. [ABSTRACT FROM AUTHOR]

An N-acylhydrazone scaffold has been used to develop new drugs with diverse biological activities, including trypanocidal activity against different strains of Trypanosoma cruzi. However, their mechanism of action is not clear, although in T. cruzi it has been suggested that the enzyme cruzain is involved. The aim in this work was to obtain new N-propionyl-N′-benzeneacylhydrazone derivatives as potential anti-T. cruzi agents and elucidate their potential mechanism of action by a molecular docking analysis and effects on the expression of the cruzain gene. Compounds 9 and 12 were the most active agents against epimastigotes and compound 5 showed better activity than benznidazole in T. cruzi blood trypomastigotes. Additionally, compounds 9 and 12 significantly increase the expression of the cruzain gene. In summary, the in silico and in vitro data presented herein suggest that compound 9 is a cruzain inhibitor. [ABSTRACT FROM AUTHOR]

Amoebiasis is caused by the protozoan Entamoeba histolytica that affects millions of people throughout the world. The standard treatment is metronidazole, however, this drug causes several side effects, and is also mutagenic and carcinogenic. Therefore, the search for therapeutic alternatives is necessary. Quinoxaline 1,4-di-N-oxides (QdNOs) derivatives have been shown to exhibit activity against different protozoan. In the present study, the effects of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives on E. histolytica proliferation, morphology, ultrastructure, and oxidative stress were evaluated, also their potential as E. histolytica thioredoxin reductase (EhTrxR) inhibitors was analyzed. In vitro tests showed that 12 compounds from n-propyl and isopropyl series, were more active (IC50 = 0.331 to 3.56 μM) than metronidazole (IC50 = 4.5 μM). The compounds with better biological activity have a bulky, trifluoromethyl and isopropyl group at R1-, R2-, and R3-position, respectively. The main alterations found in trophozoites treated with some of these compounds included changes in chromatin, cell granularity, redistribution of vacuoles with cellular debris, and an increase in reactive oxygen species. Interestingly, docking studies suggested that 7-carboxylate QdNOs derivatives could interact with amino acid residues of the NADPH-binding domain and/or the redox-active site of EhTrxR. Enzymatic assays demonstrated that selected 7-carboxylate QdNOs inhibits EhTrxR disulfide reductase activity, and diaphorase activity shows that these compounds could act as electron acceptor substrates for the enzyme. Taken together, these data indicate that among the mechanisms involved in the antiamoebic effect of the 7-carboxylate QdNOs derivatives studied, is the induction of oxidative stress and the inhibition of EhTrxR activity. [ABSTRACT FROM AUTHOR]