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

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.

Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action

“…One mechanism of action of anti-malarial agents is induction of ROS and consequent oxidative stress to kill the malaria parasite. To investigate this, a relevant model reaction using PNDA as monitoring agent [ 24 – 26 ] and an intracellular DCFH-DA assay was used [ 27 ].…”

“…Previously published procedure with slight modification was used for the determination of intracellular ROS level in P. falciparum parasites [ 27 ]. Briefly, parasitized red blood cells were treated with test compounds for 24, 48 and 72 h at 37 °C.…”

Design and synthesis of novel glycyrrhetinic acid-triazole derivatives that exert anti-plasmodial activity inducing mitochondrial-dependent apoptosis in Plasmodium falciparum

“…As previously described, an anti-plasmodial activity experiment was done in vitro using P. falciparum (ring stage) culture. 31 In a 200 mL total culture volume of 2 percent hematocrit at 1.2 percent, parasitemia in the presence of 18-b GTA. 18-b glycyrrhetinic acid and its derivatives at different concentrations (10 to 0.1 mM) were incubated for 48 hours at 37 1C under 5% CO 2 .…”

“…The ratio of reduced glutathione (GSH) and oxidized glutathione (GSSG) was evaluated fluorometrically, as reported before. 31 For 24 hours, a P. falciparum strain NF54 culture with 10% parasitemia was incubated with different concentrations ( 1 4 IC 50 , 1 2 IC 50 , IC 50 and 2IC 50 ) of compound-17 and 18b-GTA, as well as a positive control (dihydroartemisinin) at 2.4 nM. Parasite lysate was added to a reaction mixture containing sodium phosphate buffer and o-phthalaldehyde (OPT, 1 mg mL À1 ) and incubated at room temperature for 15 minutes.…”

Antioxidant Status of Children Infected with Plasmodium falciparum Malaria in Kebbi Metropolis, Northwestern Nigeria

“…Malaria is considered as one of the major life threatening disease in developing countries, despite numerous concerted efforts by the governments of various countries and other donor organizations including several drugs/combinations developed acting against the parasite [5]. Recent world malaria report released in 2020 by WHO showed that in 2019 alone, a global estimation of 229 million cases of infection and 409,000 deaths were recorded with children under the age of 5 years been the most vulnerable group as they accounted for 274,000 (67%) of all the malaria deaths worldwide [6].…”