Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors.
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.
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340 Ciudad de México, México. karla.fabiola@live.com.mx.|Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340 Ciudad de México, México. karla.fabiola@live.com.mx.
Karla Fabiola
KF
Chacón-Vargas
Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340 Ciudad de México, México. bnogueda@yahoo.com.
Benjamin
B
Nogueda-Torres
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340 Ciudad de México, México. luviasanchez@hotmail.com.
Luvia E
LE
Sánchez-Torres
Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340 Ciudad de México, México. ersuco2006@yahoo.com.mx.
Erick
E
Suarez-Contreras
Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340 Ciudad de México, México. juan_trypas@yahoo.com.mx.
Juan Carlos
JC
Villalobos-Rocha
Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro, s/n, Esq. Elías Piña, 88710 Reynosa, México. qfbyuridia@gmail.com.
Yuridia
Y
Torres-Martinez
Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro, s/n, Esq. Elías Piña, 88710 Reynosa, México. elarar0700@hotmail.com.
Edgar E
EE
Lara-Ramirez
Center of Biochemistry, Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. giulia.fiorani@studio.unibo.it.|Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. giulia.fiorani@studio.unibo.it.
Giulia
G
Fiorani
Center of Biochemistry, Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. ; luise.krauth-siegel@bzh.uni-heidelberg.de.
R Luise
RL
Krauth-Siegel
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. marialaura.bolognesi@unibo.it.
Maria Laura
ML
Bolognesi
Neglected Diseases Section, Drug R&D Unit, Center for Applied Pharmacobiology Research, University of Navarra, 31008 Pamplona, Spain. amonge@unav.es.
Antonio
A
Monge
Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro, s/n, Esq. Elías Piña, 88710 Reynosa, México. gildardors@hotmail.com.
Gildardo
G
Rivera
D001665:Binding Sites; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021261:Parasitic Sensitivity Tests; D011485:Protein Binding; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects
D011810:Quinoxalines; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
Trypanosoma cruzi; isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide; trypanothione reductase inhibitors