ESR, electrochemical, molecular modeling and biological evaluation of 4-substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones as potential anti-Trypanosoma cruzi agents.
Electrochemical and ESR studies were carried out in this work with the aim of characterizing the reduction mechanisms of 4-substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones by means of cyclic voltammetry in DMSO as aprotic solvent. Two reduction mechanisms were found for these compounds: the first, for compounds bearing a labile hydrogen by following a self-protonation mechanism (ECE steps), and the second, for compounds without labile hydrogen, based on a purely electrochemical reduction mechanism (typical of nitroheterocycles). The electrochemical results were corroborated using ESR spectroscopy allowing us to propose the hyperfine splitting pattern of the nitro-radical, which was later corroborated by the ESR simulation spectra. All these compounds were assayed as growth inhibitors against Trypanosoma cruzi: first, on the non-proliferative (and infective) form of the parasite (trypomastigote stage), and then, the ones that displayed activity, were assayed on the non-infective form (epimastigote stage). Thus, we found four new compounds highly active against T. cruzi. Finally, molecular modeling studies suggest the inhibition of the trypanothione reductase like one of the possible mechanisms involved in the trypanocidal action.
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Benjamín
B
Aguilera-Venegas
Claudio
C
Olea-Azar
Ester
E
Norambuena
Vicente J
VJ
Arán
Fernando
F
Mendizábal
Michel
M
Lapier
Juan Diego
JD
Maya
Ulrike
U
Kemmerling
Rodrigo
R
López-Muñoz
D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy; D004563:Electrochemistry / Q000379:methods; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D017672:Nitrogen Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D017672:Nitrogen Compounds; D011810:Quinoxalines; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase