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; Oscar Sánchez-Sánchez; R. Luise Krauth-Siegel; Maria Laura Bolognesi; Rogelio Gớmez-Escobedo; Benjamín Nogueda-Torres; Lenci K. Vázquez-Jiménez; Emma Saavedra; Rusely Encalada; José Carlos Espinoza-Hicks; Alma D. Paz-González; Gildardo Rivera

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, Oscar Sánchez-Sánchez, R. Luise Krauth-Siegel, Maria Laura Bolognesi, Rogelio Gớmez-Escobedo, Benjamín Nogueda-Torres, Lenci K. Vázquez-Jiménez, Emma Saavedra, Rusely Encalada, José Carlos Espinoza-Hicks, Alma D. Paz-González, Gildardo Rivera

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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).

Original language	English
Article number	13315
Journal	International Journal of Molecular Sciences
Volume	23
Issue number	21
DOIs	https://doi.org/10.3390/ijms232113315
State	Published - Nov 2022

Keywords

Chagas disease
chemical synthesis
quinoxaline-1,4-di-N-oxide
trypanothione reductase
trypomastigotes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms232113315

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González-González, A., Sánchez-Sánchez, O., Krauth-Siegel, R. L., Bolognesi, M. L., Gớmez-Escobedo, R., Nogueda-Torres, B., Vázquez-Jiménez, L. K., Saavedra, E., Encalada, R., Espinoza-Hicks, J. C., Paz-González, A. D., & Rivera, G. (2022). 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. International Journal of Molecular Sciences, 23(21), Article 13315. https://doi.org/10.3390/ijms232113315

@article{b4462237f8e443dfaf61bcdbcc13f579,

title = "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",

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{\textquoteright} 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",

author = "Alonzo Gonz{\'a}lez-Gonz{\'a}lez and Oscar S{\'a}nchez-S{\'a}nchez and Krauth-Siegel, {R. Luise} and Bolognesi, {Maria Laura} and Rogelio Gớmez-Escobedo and Benjam{\'i}n Nogueda-Torres and V{\'a}zquez-Jim{\'e}nez, {Lenci K.} and Emma Saavedra and Rusely Encalada and Espinoza-Hicks, {Jos{\'e} Carlos} and Paz-Gonz{\'a}lez, {Alma D.} and Gildardo Rivera",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = nov,

doi = "10.3390/ijms232113315",

language = "Ingl{\'e}s",

volume = "23",

journal = "International Journal of Molecular Sciences",

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González-González, A, Sánchez-Sánchez, O, Krauth-Siegel, RL, Bolognesi, ML, Gớmez-Escobedo, R, Nogueda-Torres, B, Vázquez-Jiménez, LK, Saavedra, E, Encalada, R, Espinoza-Hicks, JC, Paz-González, AD & Rivera, G 2022, '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', International Journal of Molecular Sciences, vol. 23, no. 21, 13315. https://doi.org/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. / González-González, Alonzo; Sánchez-Sánchez, Oscar; Krauth-Siegel, R. Luise et al.
In: International Journal of Molecular Sciences, Vol. 23, No. 21, 13315, 11.2022.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - González-González, Alonzo

AU - Sánchez-Sánchez, Oscar

AU - Krauth-Siegel, R. Luise

AU - Bolognesi, Maria Laura

AU - Gớmez-Escobedo, Rogelio

AU - Nogueda-Torres, Benjamín

AU - Vázquez-Jiménez, Lenci K.

AU - Saavedra, Emma

AU - Encalada, Rusely

AU - Espinoza-Hicks, José Carlos

AU - Paz-González, Alma D.

AU - Rivera, Gildardo

PY - 2022/11

Y1 - 2022/11

N2 - 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).

AB - 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).

KW - Chagas disease

KW - chemical synthesis

KW - quinoxaline-1,4-di-N-oxide

KW - trypanothione reductase

KW - trypomastigotes

UR - http://www.scopus.com/inward/record.url?scp=85141823542&partnerID=8YFLogxK

U2 - 10.3390/ijms232113315

DO - 10.3390/ijms232113315

M3 - Artículo

C2 - 36362102

AN - SCOPUS:85141823542

SN - 1661-6596

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 21

M1 - 13315

ER -

González-González A, Sánchez-Sánchez O, Krauth-Siegel RL, Bolognesi ML, Gớmez-Escobedo R, Nogueda-Torres B et al. 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. International Journal of Molecular Sciences. 2022 Nov;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

Abstract

Keywords

UN SDGs

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