TY - JOUR
T1 - Trypanocidal activity of quinoxaline 1,4 Di-N-oxide derivatives as trypanothione reductase inhibitors
AU - Chacón-Vargas, Karla Fabiola
AU - Nogueda-Torres, Benjamin
AU - Sánchez-Torres, Luvia E.
AU - Suarez-Contreras, Erick
AU - Villalobos-Rocha, Juan Carlos
AU - Torres-Martinez, Yuridia
AU - Lara-Ramirez, Edgar E.
AU - Fiorani, Giulia
AU - Krauth-Siegel, R. Luise
AU - Bolognesi, Maria Laura
AU - Monge, Antonio
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2017 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2017/2
Y1 - 2017/2
N2 - Chagas 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.
AB - Chagas 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.
KW - Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide
KW - Trypanosoma cruzi
KW - Trypanothione reductase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85014012878&partnerID=8YFLogxK
U2 - 10.3390/molecules22020220
DO - 10.3390/molecules22020220
M3 - Artículo
C2 - 28157150
SN - 1420-3049
VL - 22
JO - Molecules
JF - Molecules
IS - 2
M1 - 220
ER -