Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species
Abstract Background The challenge in anti-malarial chemotherapy is based on the emergence of resistance to drugs and the search for medicines against all stages of the life cycle of Plasmodium spp. as a therapeutic target. Nowadays, many molecules with anti-malarial activity are reported. However, f...
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ftdoajarticles:oai:doaj.org/article:8bb22a03e9fd4472accba4a3c1f38506 2023-05-15T15:12:05+02:00 Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species Leonardo Bonilla-Ramírez Silvia Galiano Miguel Quiliano Ignacio Aldana Adriana Pabón 2019-06-01T00:00:00Z https://doi.org/10.1186/s12936-019-2825-8 https://doaj.org/article/8bb22a03e9fd4472accba4a3c1f38506 EN eng BMC http://link.springer.com/article/10.1186/s12936-019-2825-8 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-019-2825-8 1475-2875 https://doaj.org/article/8bb22a03e9fd4472accba4a3c1f38506 Malaria Journal, Vol 18, Iss 1, Pp 1-13 (2019) Malaria Plasmodium Exoerythrocytic stage Quinoxaline 1 4-Di-N-oxide Cell death Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2019 ftdoajarticles https://doi.org/10.1186/s12936-019-2825-8 2023-01-08T01:24:36Z Abstract Background The challenge in anti-malarial chemotherapy is based on the emergence of resistance to drugs and the search for medicines against all stages of the life cycle of Plasmodium spp. as a therapeutic target. Nowadays, many molecules with anti-malarial activity are reported. However, few studies about the cellular and molecular mechanisms to understand their mode of action have been explored. Recently, new primaquine-based hybrids as new molecules with potential multi-acting anti-malarial activity were reported and two hybrids of primaquine linked to quinoxaline 1,4-di-N-oxide (PQ–QdNO) were identified as the most active against erythrocytic, exoerythrocytic and sporogonic stages. Methods To further understand the anti-malarial mode of action (MA) of these hybrids, hepg2-CD81 were infected with Plasmodium yoelii 17XNL and treated with PQ–QdNO hybrids during 48 h. After were evaluated the production of ROS, the mitochondrial depolarization, the total glutathione content, the DNA damage and proteins related to oxidative stress and death cell. Results In a preliminary analysis as tissue schizonticidals, these hybrids showed a mode of action dependent on peroxides production, but independent of the activation of transcription factor p53, mitochondrial depolarization and arrest cell cycle. Conclusions Primaquine–quinoxaline 1,4-di-N-oxide hybrids exert their antiplasmodial activity in the exoerythrocytic phase by generating high levels of oxidative stress which promotes the increase of total glutathione levels, through oxidation stress sensor protein DJ-1. In addition, the role of HIF1a in the mode of action of quinoxaline 1,4-di-N-oxide is independent of biological activity. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 18 1 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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English |
topic |
Malaria Plasmodium Exoerythrocytic stage Quinoxaline 1 4-Di-N-oxide Cell death Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
spellingShingle |
Malaria Plasmodium Exoerythrocytic stage Quinoxaline 1 4-Di-N-oxide Cell death Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Leonardo Bonilla-Ramírez Silvia Galiano Miguel Quiliano Ignacio Aldana Adriana Pabón Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species |
topic_facet |
Malaria Plasmodium Exoerythrocytic stage Quinoxaline 1 4-Di-N-oxide Cell death Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background The challenge in anti-malarial chemotherapy is based on the emergence of resistance to drugs and the search for medicines against all stages of the life cycle of Plasmodium spp. as a therapeutic target. Nowadays, many molecules with anti-malarial activity are reported. However, few studies about the cellular and molecular mechanisms to understand their mode of action have been explored. Recently, new primaquine-based hybrids as new molecules with potential multi-acting anti-malarial activity were reported and two hybrids of primaquine linked to quinoxaline 1,4-di-N-oxide (PQ–QdNO) were identified as the most active against erythrocytic, exoerythrocytic and sporogonic stages. Methods To further understand the anti-malarial mode of action (MA) of these hybrids, hepg2-CD81 were infected with Plasmodium yoelii 17XNL and treated with PQ–QdNO hybrids during 48 h. After were evaluated the production of ROS, the mitochondrial depolarization, the total glutathione content, the DNA damage and proteins related to oxidative stress and death cell. Results In a preliminary analysis as tissue schizonticidals, these hybrids showed a mode of action dependent on peroxides production, but independent of the activation of transcription factor p53, mitochondrial depolarization and arrest cell cycle. Conclusions Primaquine–quinoxaline 1,4-di-N-oxide hybrids exert their antiplasmodial activity in the exoerythrocytic phase by generating high levels of oxidative stress which promotes the increase of total glutathione levels, through oxidation stress sensor protein DJ-1. In addition, the role of HIF1a in the mode of action of quinoxaline 1,4-di-N-oxide is independent of biological activity. |
format |
Article in Journal/Newspaper |
author |
Leonardo Bonilla-Ramírez Silvia Galiano Miguel Quiliano Ignacio Aldana Adriana Pabón |
author_facet |
Leonardo Bonilla-Ramírez Silvia Galiano Miguel Quiliano Ignacio Aldana Adriana Pabón |
author_sort |
Leonardo Bonilla-Ramírez |
title |
Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species |
title_short |
Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species |
title_full |
Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species |
title_fullStr |
Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species |
title_full_unstemmed |
Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species |
title_sort |
primaquine–quinoxaline 1,4-di-n-oxide hybrids with action on the exo-erythrocytic forms of plasmodium induce their effect by the production of reactive oxygen species |
publisher |
BMC |
publishDate |
2019 |
url |
https://doi.org/10.1186/s12936-019-2825-8 https://doaj.org/article/8bb22a03e9fd4472accba4a3c1f38506 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 18, Iss 1, Pp 1-13 (2019) |
op_relation |
http://link.springer.com/article/10.1186/s12936-019-2825-8 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-019-2825-8 1475-2875 https://doaj.org/article/8bb22a03e9fd4472accba4a3c1f38506 |
op_doi |
https://doi.org/10.1186/s12936-019-2825-8 |
container_title |
Malaria Journal |
container_volume |
18 |
container_issue |
1 |
_version_ |
1766342825303080960 |