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, 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.

An appraisal on synthetic and pharmaceutical perspectives of quinoxaline 1,4‐di‐N‐oxide scaffold

“…Since many studies on QdNO derivatives are focused on their evolution as anti-tumor agents, one further prominent area of research is focused on anthelmintic compounds, notably those used to treat disorders namely malaria and trypanosomiasis, popularly known to be Chagas disease (Bonilla-Ramírez et al, 2019;Marin et al, 2008;Zarranz et al, 2006Zarranz et al, , 2011. Nifurtimox and benznidazole are the best-known medication for trypanosomiasis; these drugs act potent and effective in the initial phase of the disease, but in the chronic phase, their activity was found to be less active than initial phase.…”

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

“…However, several PQ‐QdNO hybrids inhibited the developmental process of P. yoelii within HepG2‐CD81 cells by promoting ROS formation in the parasite and did not produce any mitochondrial depolarization, suggesting a mechanism of damage independent of mitochondrial signaling. The increase in ROS production was also associated with an increase in total glutathione levels (tGSH) in the infected cells and the alteration of the expression of some molecules related to oxidative stress, such as glutathione peroxidase 1 (GPX1) and DJ‐1 protein (Bonilla‐Ramírez et al., 2019).…”

Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene Phytotherapeutics

“…Failure to convert heme to its biocrystallization or biomineralization form will oxidize the parasite food vacuole membranes destroying it in the process. Chloroquine and other 4-aminoquinolines use this principle to dislocate parasite proliferation by inhibiting heme biocrystallization in pRBC's and increasing OS [85][86][87][88][89].…”