Biological activity of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors

Soto‐Sanchez, Jacqueline; Caro-Gómez, Luis A; Paz-González, Alma D.; Marchat, Laurence A.; Rivera, Gildardo; Moo-Puc, Rosa; Arias, Diego Gustavo; Ramírez‐Moreno, Esther

doi:10.1007/s00436-019-06580-8

Cited by 11 publications

(13 citation statements)

References 53 publications

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“…Interestingly, the quinoxalines T-001 or T-017 also produced the overexpression of proteins of intracellular traffic: the protein with TBC domain (C4M7P5) and the protein of the Rab GTPase family (Q5NT06), both involved in the dynamics of the vesicular fusion (some Rabs contain the TBC domain), the ADPribosylation factor (ARFs) (Q1EQ60), a regulator of vesicle formation in intracellular traffic (Serbzhinskiy et al, 2015) and the putative vesicle-fusion ATPase (C4LYS4), which catalyzes the fusion of transport vesicles within the cisternae of the Golgi apparatus (Qiu, 2012). The deregulation of these proteins that participate in the intracellular traffic could explain the presence of a higher number of vacuoles and vesicles that we previously reported in E. histolytica trophozoites treated with T-001 and T-017 (Soto-Sańchez et al, 2020). Other studies carried out in T. cruzi epimastigotes also evidenced that QdNOs produced an increase in the number of vesicles in the cytoplasm was also found, as well as alterations in the Golgi apparatus, which suggest that QdNOs alters the secretory pathway in this parasite (Rodrigues et al, 2014).…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, by comparing the antiamebic activity and cytotoxic activity in Vero cells, the compounds that presented the best selectivity index (SI) were T-017 (SI> 51.81), T-014 (SI> 53.19), T-001 (IS> 68.02) and T-016 (IS> 70.92), suggesting that these molecules could be valuable candidates as antiamebic drugs ( Duque-Montaño et al., 2013 ). Recently, Soto-Sánchez et al., 2020 , showed that these four 7-carboxylate QdNOs produce morphological changes in E. histolytica trophozoites, including chromatin remodelling, cellular granularity and redistribution of vacuoles, as well as an increase in reactive oxygen species (ROS). Additionally, molecular docking analysis indicated that the compounds can interact with amino acid residues of the NADH-binding domain and the redox active site of E. histolytica thioredoxin reductase (EhTrxR); complementary enzyme assays showed that the compounds inhibit its disulfide reductase and diaphorase activity, acting as electron acceptor substrate for this enzyme.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic and Functional Analysis of the Effects of Quinoxaline Derivatives on Entamoeba histolytica

Avila-Bonilla

López-Sandoval

Soto‐Sanchez

et al. 2022

Front. Cell. Infect. Microbiol.

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Quinoxalines are heterocyclic compounds that contain a benzene ring and a pyrazine ring. The oxidation of both nitrogen of the pyrazine ring results in quinoxaline derivatives (QdNO), which exhibit a variety of biological properties, including antiparasitic activity. However, its activity against Entamoeba histolytica, the protozoan that causes human amebiasis, is poorly understood. Recently, our group reported that various QdNOs produce morphological changes in E. histolytica trophozoites, increase reactive oxygen species, and inhibit thioredoxin reductase activity. Notably, T-001 and T-017 derivatives were among the QdNOs with the best activity. In order to contribute to the characterization of the antiamebic effect of QdNOs, in this work we analyzed the proteomic profile of E. histolytica trophozoites treated with the QdNOs T-001 and T-017, and the results were correlated with functional assays. A total number of 163 deregulated proteins were found in trophozoites treated with T-001, and 131 in those treated with T-017. A set of 21 overexpressed and 24 under-expressed proteins was identified, which were mainly related to cytoskeleton and intracellular traffic, nucleic acid transcription, translation and binding, and redox homeostasis. Furthermore, T-001 and T-017 modified the virulence of trophozoites, since they altered their erythrophagocytosis, migration, adhesion and cytolytic capacity. Our results show that in addition to alter reactive oxygen species, and thioredoxin reductase activity, T-001 and T-017 affect essential functions related to the actin cytoskeleton, which eventually affects E. histolytica virulence and survival.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Proteomic and Functional Analysis of the Effects of Quinoxaline Derivatives on Entamoeba histolytica

Avila-Bonilla

López-Sandoval

Soto‐Sanchez

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Compounds with better bioactivity ( 5c and 3k ) have a CF 3 group at R3‐position and an isopropyl at R7‐position. The presence of an n‐propyl group at R7‐position did not seem to favor the biological activity of the compounds (Soto‐Sánchez et al., 2020).…”

Section: Quinoxaline and Qdnos Derivativesmentioning

confidence: 99%

“…In a previous work carried out by our research team, we observed that 7‐carboxylate QdNOs derivatives inhibited the disulfide reductase activity of E. histolytica thioredoxin reductase (EhTrxR). Molecular docking studies indicated that these compounds bind mainly by hydrophobic interactions with amino acids from the catalytic site of EhTrxR (Soto‐Sánchez et al., 2020). The Trx system provides the electrons to peroxiredoxins (Prxs) to remove reactive oxygen and nitrogen species (Lu & Holmgren, 2014).…”

Section: Quinoxaline and Qdnos Derivatives Main Targetsmentioning

confidence: 99%

Current status of quinoxaline and quinoxaline 1,4‐di‐N‐oxides derivatives as potential antiparasitic agents

Soto‐Sanchez

Ospina-Villa

2021

Chem Biol Drug Des

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Parasitic diseases are a public health problem, especially in developing countries where millions of people are affected every year. Current treatments have several drawbacks: emerging resistance to the existing drugs, lack of efficacy, and toxic side effects. Therefore, new antiparasitic drugs are urgently needed to treat and control diseases that affect human health, such as malaria, Chagas disease, leishmaniasis, amebiasis, giardiasis schistosomiasis, and filariasis, among others. Quinoxaline is a compound containing a benzene ring and a pyrazine ring. The oxidation of both pyrazine ring nitrogens allows the obtention of quinoxaline 1,4-di-N-oxides (QdNOs) derivatives. By modifying the chemical structure of these compounds, it is possible to obtain a wide variety of biological properties. This review investigated the activity of quinoxaline derivatives and QdNOs against different protozoan parasites and helminths. We also cover the structure-activity relationship (SAR) and summarize the main findings related to their mechanisms of action from published works in recent years. However, further studies are needed to determine specific molecular targets. This review aims to highlight the new development of antiparasitic drugs with better pharmacological profiles than current treatments.

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“…[ 6,7 ] Currently, there are several works concerning the development of new antiamoebic drugs, such as the searching of compound libraries, that propose different therapeutic targets with better advantages as compared with metronidazole. [ 8–12 ] Also, some works have proposed a selective target, such as the enzyme triosephosphate isomerase (TIM) [ 13 ] ; this glycolytic enzyme has been used as a therapeutic target for the development of new drugs against various pathogenic organisms, such as Trypanosoma cruzi , Trypanosoma brucei , E. histolytica , Giardia duodenalis , Trichomonas vaginalis , Clostridium perfringens , among others. [ 14–24 ] In addition, other researchers are looking for the repositioning of commercial drugs as antiparasitics.…”

Section: Introductionmentioning

confidence: 99%

Amoebicidal effect of 5,5′‐[(4‐nitrophenyl)methylene]bis‐6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone), a new drug against Entamoeba histolytica

Vique‐Sánchez¹,

Jiménez-Pineda

Benítez‐Cardoza

2020

Archiv der Pharmazie

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Entamoeba histolytica is a cosmopolitan protozoan parasite that can produce infections in the intestine and some organs (liver, lungs, and brain), with worldwide prevalence. There are treatments against E. histolytica (antiparasitics), but as the drugs used in these treatments have presented some type of resistance and/or side effects, there are cases with complications of this disease. Therefore, it is necessary to develop new drugs aimed at a specific therapeutic target against this parasite. Here, we used the compound 5,5′‐[(4‐nitrophenyl)methylene]bis(6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone) in the patenting process (called D4). D4 has a reported specific use against a glycolytic enzyme, the triosephosphate isomerase of Trichomonas vaginalis (TvTIM). We determined that D4 has an amoebicidal effect in in vitro cultures, with an IC50 value of 18.5 µM, and we proposed a specific site of interaction (Lys77, His110, Gln115, and Glu118) in the triosephosphate isomerase of E. histolytica (EhTIM). Furthermore, compound D4 has favorable experimental and theoretical toxicity results. Therefore, D4 should be further investigated as a potential drug against E. histolytica.

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Biological activity of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors

Cited by 11 publications

References 53 publications

Proteomic and Functional Analysis of the Effects of Quinoxaline Derivatives on Entamoeba histolytica

Proteomic and Functional Analysis of the Effects of Quinoxaline Derivatives on Entamoeba histolytica

Current status of quinoxaline and quinoxaline 1,4‐di‐N‐oxides derivatives as potential antiparasitic agents

Amoebicidal effect of 5,5′‐[(4‐nitrophenyl)methylene]bis‐6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone), a new drug against Entamoeba histolytica

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