Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors
| Autor: | Erick Suarez-Contreras, Luvia Enid Sánchez-Torres, Giulia Fiorani, Edgar E. Lara-Ramírez, Yuridia Torres-Martinez, Juan Carlos Villalobos-Rocha, Karla Fabiola Chacón-Vargas, Benjamín Nogueda-Torres, Maria Laura Bolognesi, R. Krauth-Siegel, Gildardo Rivera, Antonio Monge |
|---|---|
| Přispěvatelé: | Chacón-Vargas, Karla Fabiola, Nogueda-Torres, Benjamin, Sánchez-Torres, Luvia E., Suarez-Contreras, Erick, Villalobos-Rocha, Juan Carlo, Torres-Martinez, Yuridia, Lara-Ramirez, Edgar E., Fiorani, Giulia, Krauth-Siegel, R Luise, Bolognesi, Maria Laura, Monge, Antonio, Rivera, Gildardo |
| Rok vydání: | 2017 |
| Předmět: |
Parasitic Sensitivity Test
0301 basic medicine Molecular Conformation Pharmaceutical Science 01 natural sciences Analytical Chemistry chemistry.chemical_compound Trypanothione reductase inhibitor Parasitic Sensitivity Tests Drug Discovery NADH NADPH Oxidoreductases isopropyl quinoxaline-7-carboxylate 1 4-di-N-oxide chemistry.chemical_classification Trypanocidal Agent Chemistry Medicine (all) trypanothione reductase inhibitors Trypanocidal Agents Molecular Docking Simulation Chemistry (miscellaneous) Molecular Medicine Lead compound Protein Binding Quinoxaline Stereochemistry Trypanosoma cruzi Chemical structure Molecular Dynamics Simulation Article lcsh:QD241-441 Inhibitory Concentration 50 Structure-Activity Relationship 03 medical and health sciences lcsh:Organic chemistry Quinoxalines Structure–activity relationship Physical and Theoretical Chemistry IC50 Trypanocidal agent Binding Sites 010405 organic chemistry Organic Chemistry Binding Site 0104 chemical sciences 030104 developmental biology Enzyme NADH NADPH Oxidoreductase Isopropyl |
| Zdroj: | Molecules; Volume 22; Issue 2; Pages: 220 Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry Molecules, Vol 22, Iss 2, p 220 (2017) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules22020220 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|