4-Chlorothymol Exerts Antiplasmodial Activity Impeding Redox Defense System in Plasmodium falciparum

Saurabh Kumar,Sudeep Tandon,Mahendra P. Darokar,Anirban Pal,Pooja Rani Mina,Ravi Kumar,Ateeque Ahmad

doi:10.3389/fphar.2021.628970

Saurabh Kumar, Sudeep Tandon + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2021.628970

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Abstract

Malaria remains one of the major health concerns due to the resistance of Plasmodium species toward the existing drugs warranting an urgent need for new antimalarials. Thymol derivatives were known to exhibit enhanced antimicrobial activities; however, no reports were found against Plasmodium spp. In the present study, the antiplasmodial activity of thymol derivatives was evaluated against chloroquine-sensitive (NF-54) and -resistant (K1) strains of Plasmodium falciparum. Among the thymol derivatives tested, 4-chlorothymol showed potential activity against sensitive and resistant strains of P. falciparum. 4-Chlorothymol was found to increase the reactive oxygen species and reactive nitrogen species level. Furthermore, 4-chlorothymol could perturb the redox balance by modulating the enzyme activity of GST and GR. 4-Chlorothymol also showed synergy with chloroquine against chloroquine-resistant P. falciparum. 4-Chlorothymol was found to significantly suppress the parasitemia and increase the mean survival time in in vivo assays. Interestingly, in in vivo assay, 4-chlorothymol in combination with chloroquine showed higher chemosuppression as well as enhanced mean survival time at a much lower concentration as compared to individual doses of chloroquine and 4-chlorothymol. These observations clearly indicate the potential use of 4-chlorothymol as an antimalarial agent, which may also be effective in combination with the existing antiplasmodial drugs against chloroquine-resistant P. falciparum infection. In vitro cytotoxicity/hemolytic assay evidently suggests that 4-chlorothymol is safe for further exploration of its therapeutic properties.

Highlights

Malaria remains one of the major health concerns especially in tropical countries, despite the fact that numerous drugs/combinations are available against the protozoan parasite Plasmodium species (Pink et al, 2005)
MO, United States), and Albumax II, Roswell Park Memorial Institute 1,640 (RPMI1640), Dulbecco’s modified eagle medium (DMEM), fetal bovine serum (FBS), and fungizone were purchased from Gibco (Grand Island, United States)
Malaria is one of the most distressing parasitic diseases despite the availability of numerous drugs acting against the protozoan parasite Plasmodium spp. in its human host

Summary

Introduction

Malaria remains one of the major health concerns especially in tropical countries, despite the fact that numerous drugs/combinations are available against the protozoan parasite Plasmodium species (Pink et al, 2005). Malarial drug resistance is further posing challenges as first-line combination therapy is becoming ineffective. New strategies are required to overcome the challenges of drug resistance in malaria parasites (Fairhurst et al, 2012). P. falciparum degrades hemoglobin into free heme and globins generating reactive oxygen species (ROS) in the process (Deshmukh and Trivedi, 2013). ROS is generated into mitochondria through various metabolic processes (Trivedi et al, 2005; Van Dooren et al, 2006). In P. falciparum, ROS is detoxified majorly through glutathione redox system involving various enzymes such as glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) (Müller, 2004; Müller, 2015)

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