Antileishmanial mode of action of lapachol and plumbagin

Plumbagin, a naphthoquinone first isolated from species of the genus Plumbago, and lapachol, a prenylated hydroxynaphthoquinone encountered in Tabebuia avellanedae (Bignoniaceae), were reported as antifungal, antibacterial, anticancer and antileishmanial agents [1, 2]. It has been suggested that the antileishmanial activity of these naphthoquinones is due to the generation of reactive oxygen species [3]. The aim of this investigation was to evaluate the antileishmanial activity of lapachol and plumbagin with a closer view on their mode of action. Lapachol exhibited prominent antileishmanial activity against L. major promastigotes with an IC50 value of 8µg/ml (33µM) and showed a moderate activity against amastigotes as evident from an IC50 value of 28µg/ml (115µM). It did not show any cytotoxicity on macrophages as host cells even at high concentrations (EC50 >72µg/ml, 300µM). On the other hand plumbagin was significantly more effective against both extra- and intracellular L. major parasites (IC50 0.5µg/ml, 2.6µM), but was relatively more cytotoxic on macrophages (1.5µg/ml; 8µM). Plumbagin and lapachol did not induce NO release in infected macrophages. Both compounds were found to be similarly antileishmanicidal when incubated with or without the iNOS inhibitor L-NMMA. While plumbagin did not show any antileishmanial effects in the presence of glutathione plus ascorbic acid, no difference in activity was found for lapachol. This finding suggests that lapachol and plumbagin mediate their antileishmanial activities by different mode of actions and independent from NO production.

References: 1. Hussain, H et al. (2007), Arkivoc: 145–171.

2. Croft S et al. (1985), Annal Trop Med Parasitol 79: 651–653.

3. Inbaraj JJ, Chignell CF (2004), Chem ResToxicol. 17: 55–62.