Silymarin, a polyphenolic flavonoid impedePlasmodium falciparumgrowth through interaction with heme

Abstract

A polyphenolic flavonoid, Silymarin isolated from Silybum marianum is widely known for its hepatoprotective action. In the present study anti-plasmodial activity of Silymarin has been demonstrated for the first time having IC 50 of 14±0.33 μM against the NF-54 strain of P. falciparum with high selectivity index (>100). The parasitostatic action is exerted through inhibition of β-hematin/hemozoin formation which is due to the interaction (Kd=3.63±0.9µM) of silymarin with free heme in a Stoichiometry of 1:1 silymarin: heme complex resulting into heme-induced membrane damage in the parasite. Silymarin could hinder the glutathione and hydrogen peroxide-induced heme detoxification. Silymarin also induces apoptosis in the parasite through the elevation of caspase-3 level in a dose-dependent manner. Results from the docking studies suggest that silymarin interacts with heme.

Health Benefits of Silybum marianum: Phytochemistry, Pharmacology, and Applications

“…23 Silymarin reduces the viability of P. falciparum with a high selectivity index by inducing membrane damage and apoptosis via interaction with heme. 24 Leishmania species are obligate intracellular parasites of mononuclear phagocytes transmitted by phlebotomine sandflies. 25 Dehydroisosilybin exhibits antiproliferative effect against Leishmania promastigotes in vitro, but it does not inhibit the multiplication of parasites at the intracellular stage (Table 1).…”

“…Silymarin reduces the viability of P. falciparum with a high selectivity index by inducing membrane damage and apoptosis via interaction with heme Leishmania species are obligate intracellular parasites of mononuclear phagocytes transmitted by phlebotomine sandflies .…”

Future antimalarials fromArtemisia? A rationale for natural product mining against drug-refractoryPlasmodiumstages

“…Mechanistically, antiplasmodial flavonoids are believed to exert inhibition by binding to the free heme present in the food vacuole, thereby preventing its detoxification into hemozoin. 117–119 While such a scenario may apply to the actively digesting asexual blood stages ( e.g. , trophozoites) and immature gametocytes, 120 mimicking the action of heme-binding antimalarials ( e.g.…”

“…Mechanistically, antiplasmodial avonoids are believed to exert inhibition by binding to the free heme present in the food vacuole, thereby preventing its detoxication into hemozoin. [117][118][119] While such a scenario may apply to the actively digesting asexual blood stages (e.g., trophozoites) and immature gametocytes, 120 mimicking the action of heme-binding antimalarials (e.g., chloroquine, lumefantrine) against these parasite stages, 37,41 it is irrelevant in liver stages. Several antiplasmodial avonoids present (e.g., quercetin, luteolin, cynaroside) or suspected (e.g., kaempferol, tamarixetin) in the infusions of A. annua and/or A. afra could target the Plasmodium apicoplast, as they inhibit FabG, FabZ and/or FabI in vitro at micromolar concentrations.…”

The acetone crude extract of Quercus infectoria (Olivier) galls alters pH of the digestive vacuole of the malaria parasite, Plasmodium falciparum

“…Phenolic glycosides isolated from Flacourtia indica commonly known as governor's plum have been shown to act through the inhibition of heme polymerization and β-hematin formation (Singh et al, 2017). The polyphenolic flavonoid, silymarin demonstrated antimalarial activity by forming soluble complexes with free heme, thereby blocking the formation of hemozoin (Mina et al, 2020). Meanwhile, xanthones have been proposed to inhibit heme polymerization (Ke et al, 2017).…”