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 reducta...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
1 February 2017
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| In: |
Molecules
Year: 2017, Volume: 22, Issue: 2 |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules22020220 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.3390/molecules22020220 Verlag, Volltext: https://www.mdpi.com/1420-3049/22/2/220 
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| Author Notes: | Karla Fabiola Chacón-Vargas, Benjamin Nogueda-Torres, Luvia E. Sánchez-Torres, Erick Suarez-Contreras, Juan Carlos Villalobos-Rocha, Yuridia Torres-Martinez, Edgar E. Lara-Ramirez, Giulia Fiorani, R. Luise Krauth-Siegel, Maria Laura Bolognesi, Antonio Monge and Gildardo Rivera |
| Summary: | 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. |
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| Item Description: | Gesehen am 12.11.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules22020220 |