The Antiparasitic Compound Licochalcone A Is a Potent Echinocytogenic Agent That Modifies the Erythrocyte Membrane in the Concentration Range Where Antiplasmodial Activity Is Observed

Abstract

The well-known antiparasitic compound licochalcone A is a potent membrane-active agent that transforms normal erythrocytes into echinocytes in parallel with the inhibition of growth of Plasmodium falciparum cultures, the in vitro antiplasmodial effect apparently being an indirect effect on the host cell. In vitro experiments with synchronous cultures demonstrate that inhibition of invasion is the principal mechanism of growth inhibition. The erythrocyte membrane-modifying effect was also transiently observed in vivo in mice after intravenous administration.Licochalcone A (Fig. 1) was originally isolated (39, 44) as a constituent of roots and rhizomes of various species of Glycyrrhiza L. (licorice root), and its structure was confirmed by synthesis (20,22,44). Subsequent studies resulted in reports of a variety of biological effects of licochalcone A, notably antibacterial (13-15, 17, 18, 36, 43), antileishmanial (3, 4, 8, 34, 45, 46), and antiplasmodial (6, 7, 23) ones. Thus, the compound inhibited growth of Plasmodium falciparum strain 3D7 parasites in vitro with 50% inhibitory concentrations (IC 50 s) of 5.6 Ϯ 0.6 M (35) and reduced parasitemia in mice infected with Plasmodium yoelii (7,23). Compounds related to licochalcone A exhibited comparable antiplasmodial activity in vitro (5, 35).The licochalcone A used in the present work was synthesized as previously described (22,33,44). The purity of the compound was assessed by high-performance liquid chromatography (C 18 column, acetonitrile gradient in water) and 600-MHz 1 H nuclear magnetic resonance and was higher than 99.9%. Determination of the in vitro IC 50 (Fig. 2) for P. falciparum strain 3D7 (initial parasitemia, 1.5%) was performed as previously described (49) using 12 concentrations (each used in triplicate) in the range from 0.098 to 25.0 g/ml (0.29 to 73.9 M); an average IC 50 calculated from three independent determinations was 2.10 Ϯ 0.56 g/ml (6.21 Ϯ 1.65 M), which was practically identical to the reported value (35). Microscopic examination of the cultures showed the presence of dead merozoites and ruptured schizonts at concentrations of 1.56 g/ml and above, and no internal parasites beyond the ring stage were observed.However, simultaneously with the growth inhibition, the exposure of the parasite cultures to licochalcone A caused pronounced membrane perturbations of the erythrocytes in which the parasites grow. The effect of licochalcone A on erythrocytes was the same regardless of whether parasitized or nonparasitized erythrocytes were used and was observed in the same concentration range as that of the in vitro antiplasmodial activity. In order to assess these membrane effects systematically, nonparasitized erythrocytes were incubated with licochalcone A at five different concentrations (0.098, 1.56, 3.13, 5.0, and 25.0 g/ml) for 48 h as in the growth inhibition assay. The deformations of the cell shape were investigated by light microscopy after fixation to glass slides with methanol followed by staining with Giemsa as well as by the hangi...

Up-Regulation of Licochalcone A Biosynthesis and Secretion by Tween 80 in Hairy Root Cultures of Glycyrrhiza uralensis Fisch

“…Licochalcone A (Fig. 1), a major phenolic constituent, has drawn pharmacological attention in the recent past due to its antibacterial [9,22], antiprotozoan [35], and antitumor properties [8]. These properties are responsible for the growing demand for Glycyrrhiza and its flavonoid extracts.…”

Licochalcones suppress degranulation by decreasing the intracellular Ca2+ level and tyrosine phosphorylation of ERK in RBL-2H3 cells

“…Licochalcone A (Lico A), a retrochalcone isolated from the root of Xinjiang liquorice [8], is abundant in the residue of extract after isolating of glycyrrhizin and is known to be a species-specific component of Glycyrrhiza inflata [9]. It has been reported that Lico A has various biological activities, such as anti-inflammatory activity [10,11], anti-oxidic activity [12], antimalarial activity [13] and anti-leishmanial activity [14]. Licochalcone B (Lico B), licochalcone C (Lico C) and licochalcone D (Lico D) were isolated also from the root of Glycyrrhiza inflata [8,15,16] but biological activities of these retrochalcones have not been well examined.…”

Synthesis and antimalarial activity of 7‐benzylamino‐1‐isoquinolinamines

“…Treatment of 7-nitro-isoquinoline (6) with m-chloroperbenzoic acid in acetone gave 7-nitroisoquinoline-2-oxide (7) [18]. Subsequent reaction with p-toluenesulfonyl chloride gave 1-chloro-7-nitroisoquinoline (8), which in turn was reacted with ethanolamine to provide 7-nitro-1-isoquinolinamine (9) [18]. This was purified by alumina column chromatography, and then hydrogenated to give 1,7-isoquinolinediamine (3) [17].…”

“…Several groups have studied the relationship between the structure of substituted 2-propen-1-ones and their antimalarial activity. Since the emerging relationship does not correlate with that between structure and the inhibition of any known antimalarial target, the mechanism by which the chalcones act appears to be distinct from the established mechanisms [7][8][9]. During our investigation of the relationship between 1,3-diaryl-2-propen-1-one structure and antimalarial activity [10], we generated a computer model of the structural and electronic features required in such compounds to maximize in vitro antimalarial activity [11].…”