Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors
AbstractChagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity. View Full-Text
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Chacón-Vargas, K.F.; Nogueda-Torres, B.; Sánchez-Torres, L.E.; Suarez-Contreras, E.; Villalobos-Rocha, J.C.; Torres-Martinez, Y.; Lara-Ramirez, E.E.; Fiorani, G.; Krauth-Siegel, R.L.; Bolognesi, M.L.; Monge, A.; Rivera, G. Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors. Molecules 2017, 22, 220.
Chacón-Vargas KF, Nogueda-Torres B, Sánchez-Torres LE, Suarez-Contreras E, Villalobos-Rocha JC, Torres-Martinez Y, Lara-Ramirez EE, Fiorani G, Krauth-Siegel RL, Bolognesi ML, Monge A, Rivera G. Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors. Molecules. 2017; 22(2):220.Chicago/Turabian Style
Chacón-Vargas, Karla F.; Nogueda-Torres, Benjamin; Sánchez-Torres, Luvia E.; Suarez-Contreras, Erick; Villalobos-Rocha, Juan C.; Torres-Martinez, Yuridia; Lara-Ramirez, Edgar E.; Fiorani, Giulia; Krauth-Siegel, R. L.; Bolognesi, Maria L.; Monge, Antonio; Rivera, Gildardo. 2017. "Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors." Molecules 22, no. 2: 220.
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