Role of Single-Electron Oxidation Potential and Lipophilicity in the Antiplasmodial in vitro Activity of Polyphenols: Comparison to Mammalian Cells

Abstract

In spite of extensive studies, the structure-activity relationships in the action of polyphenols against the malaria parasite Plasmodium falciparum are poorly understood so far. As the mammalian cell cytotoxicity of polyphenols shows a negative dependence on the potential of the phenoxyl radical/phenol redox couple (E 2 7 ), due to the involvement of prooxidant events, and a positive dependence on the octanol/water distribution coefficient at pH 7.0 (log D), we examined the role of these parameters in their antiplasmodial in vitro activity. We found that the concentrations of hydroxybenzenes causing 50% inhibition of the growth of P. falciparum strain FcB1 (IC 50 ) are described by the regression log IC 50 (μm) = 0.36 + 1.81 E , where CL 50 is the compound concentration for 50% cell survival] than on their antiplasmodial activity. Although it is unclear whether the prooxidant action is the main factor in the antiplasmodial action of polyphenols or not, our data showed that the ease of their oxidation (decrease in E 2 7 ) may enhance their activity. On the other hand, the different sensitivity of the mammalian cell cytotoxicity and the antiplasmodial activity of the hydroxybenzenes to their E 2 7 values implied that compounds with high oxidation potential may be used as relatively efficient antiplasmodial agents with low mammalian cell cytotoxicity.

Correlation between mammalian cell cytotoxicity of flavonoids and the redox potential of phenoxyl radical/phenol couple.

“…The obtained QSARs and the effects of antioxidants, prooxidants, and inhibitors of cytochromes P-450 and COMT (Figs. 3,4) for flavonoids are similar to those observed in the action of polyhydroxybenzenes in the same cell lines (Nemeikaitė-Čėnienė et al, 2005;Grellier et al, 2008). It shows that both groups of polyphenolic antioxidants may share the same main mechanism(s) of prooxidant cytotoxicity.…”

“…It points to a common prooxidant cytotoxicity mechanism of both compounds. The concentrations of flavonoids causing 50% death of FLK and MH-22a cells (cL 50 ), determined in the present work or taken from our previous studies (Nemeikaitė-Čėnienė et al, 2005;Grellier et al, 2008), and the previously obtained cL 50 values of flavonoids in human promyelocytic leukemic cells (line HL-60) (Nemeikaitė-Čėnienė et al, 2005;Grellier et al, 2008) are given in Table 2, together with their E 7 (Q •-/QH 2 ) (calc.) values.…”

“…One may expect that the cytotoxicity of flavonoids, if determined by their prooxidant action, may increase with a decrease in the redox potential of the semiquinone/ hydroquinone (or phenoxyl radical/phenol) couple (E 7 (Q •-/QH 2 )). This relationship has been demonstrated for a related group of antioxidants, polyhydroxybenzenes (Nemeikaitė-Čėnienė et al, 2005;Grellier et al, 2008). It reflects the relative ease of formation of prooxidant oxidation products or ROS by hydroquinones and other polyphenols, because the rates of their oxidation by cytochromes, Fe 3+ , ferritin, or oxygen increase with a decrease in their E 7 (Q •-/QH 2 ) (Rich & Bendall, 1980;Rich, 1982;O'Brien, 1991;Hynes & Coincemainn, 2002).…”

“…Cell culture cytotoxicity studies. Cultures of bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) and murine hepatoma (line MH-22) were grown and maintained at 37°C in Eagle's medium or in DMEM medium, respectively, supplemented with 10% fetal bovine serum and antibiotics, as described (Nemeikaitė-Čėnienė et al, 2005;Grellier et al, 2008). In the cytotoxicity experiments, cells (2.5×10 4 /ml FLK, and 3.0×10 4 /ml MH-22a) were seeded on 18×18 mm glass slides in 5-ml flasks either in the presence or in the absence of compounds, and were grown for 24 h. Then, the slides were rinsed 3-4 times with phosphate buffered saline and stained with Trypan blue.…”

Exploring the powerful phytoarsenal of white grape marc against bacteria and parasites causing significant diseases

“…In other cases, natural polyphenols were used to complement activities of other anti-parasitic treatments as it is the case for resveratrol combined to sulfamethoxazoletrimethoprim against T. gondii (Bottari et al 2015). Anti-Plasmodium activity has also been tested several times by using polyphenols (Khasanah et al 2017;Dohutia et al 2017;Grellier et al 2008). Our results demonstrate, for the first time, that both extracts of white grape marc reduce T. gondii infection in HFFs and that P. falciparum growth is also severely affected.…”