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. 2022 Nov 1;23(21):13315.
doi: 10.3390/ijms232113315.

In Vitro and In Silico Analysis of New n-Butyl and Isobutyl Quinoxaline-7-carboxylate 1,4-di- N-oxide Derivatives against Trypanosoma cruzi as Trypanothione Reductase Inhibitors

Alonzo González-González  1 , Oscar Sánchez-Sánchez  1 , R Luise Krauth-Siegel  2 , Maria Laura Bolognesi  3 , Rogelio Gớmez-Escobedo  4 , Benjamín Nogueda-Torres  4 , Lenci K Vázquez-Jiménez  1 , Emma Saavedra  5 , Rusely Encalada  5 , José Carlos Espinoza-Hicks  6 , Alma D Paz-González  1 , Gildardo Rivera  1
Affiliations

In Vitro and In Silico Analysis of New n-Butyl and Isobutyl Quinoxaline-7-carboxylate 1,4-di- N-oxide Derivatives against Trypanosoma cruzi as Trypanothione Reductase Inhibitors

Alonzo González-González et al. Int J Mol Sci. .

Abstract

American trypanosomiasis is a worldwide health problem that requires attention due to ineffective treatment options. We evaluated n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives against trypomastigotes of the Trypanosoma cruzi strains NINOA and INC-5. An in silico analysis of the interactions of 1,4-di-N-oxide on the active site of trypanothione reductase (TR) and an enzyme inhibition study was carried out. The n-butyl series compound identified as T-150 had the best trypanocidal activity against T. cruzi trypomastigotes, with a 13% TR inhibition at 44 μM. The derivative T-147 behaved as a mixed inhibitor with Ki and Ki' inhibition constants of 11.4 and 60.8 µM, respectively. This finding is comparable to the TR inhibitor mepacrine (Ki = 19 µM).

Keywords: Chagas disease; chemical synthesis; quinoxaline-1,4-di-N-oxide; trypanothione reductase; trypomastigotes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The synthetic pathway for forming the n-butyl and isobutyl quinoxaline 1,4-di-N-oxide series from the Beirut reaction.
Figure 2
Figure 2
Two-dimensional interaction representation for T-147, a potential TcTR inhibitor; dashed grey line: hydrophobic interaction; solid blue line: hydrogen bond; solid golden line: salt bridge; solid light cyan line: halogen interaction.
Figure 3
Figure 3
n-butyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives tested for TR inhibitory activity and similarity to the known inhibitor, T-085.
Figure 4
Figure 4
Lineweaver–Burk plot of TR inhibition by the compound T-147.
Figure 5
Figure 5
RMSD graph for fluctuations over time for TcTR complexes and free TcTR; fluctuations: T-147 (0.79–12.28 Å), mepacrine (1.02–8.10 Å), and TcTR (0.33–2.22 Å).
Figure 6
Figure 6
RMSF graph for fluctuations over time for mepacrine-TcTR and T-147-TcTR complexes, and apo-TcTR, blue spiral (alpha helix), green triangle (beta sheet), in between space (loop).
Figure 7
Figure 7
The radius of gyration graph for molecular dynamics over time for mepacrine-TcTR (yellow) and T-147-TcTR (green) complexes, and apo-TcTR (red).
Figure 8
Figure 8
RMSD graph for fluctuations over time for hGR complexes; fluctuation: T-147 (0.81–14.31 Å), mepacrine (0.91–11.3 Å), and hGR (0.32–2.93 Å).
Figure 9
Figure 9
RMSF graph for fluctuations over time for mepacrine-hGR, T-147-hGR complexes, and apo-hGR, blue spiral (alpha helix), green triangle (beta sheet), in between space (loop).
Figure 10
Figure 10
The radius of gyration graph for molecular dynamics over time for mepacrine-hGR (yellow) and T-147-hGR complexes (green), and apo-hGR (red).
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