Elsevier

Phytochemistry Letters

Volume 1, Issue 4, 12 December 2008, Pages 171-174
Phytochemistry Letters

Antiplasmodial and leishmanicidal activity of biflavonoids from Indian Selaginella bryopteris

https://doi.org/10.1016/j.phytol.2008.09.003Get rights and content

Abstract

A series of eleven biflavonoids containing amentoflavone and hinokiflavone derivatives from the Indian medicinal herb Selaginella bryopteris has been investigated for their antiprotozoal activity using in vitro assays against the K1 strain of Plasmodium falciparum, Leishmania donovani, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. The highest antiprotozoal activity was displayed by 7,4′,7″-tri-O-methylamentoflavone which exhibited an IC50 of 0.26 μM. This compound showed no significant cytotoxicity (IC50 > 150 μM) evaluated using L-6 cells. The strongest activity against Leishmania was detected for 2,3-dihydrohinokiflavone (IC50 = 1.6 μM), whereas for Trypanosoma no significant activity was observed (IC50 > 12.5 μg/mL for the extract). To evaluate the in vivo activity against Plasmodium of the most active compound, trimethylated amentoflavones were obtained by partial synthesis starting from amentoflavone. The synthesized mixture of trimethylated amentoflavones did not show activity in the Plasmodium berghei mouse model against female NMRI mice at 50 mg/kg.

Graphical abstract

Eleven derivatives of amentoflavone and hinokiflavone from the Indian herb Selaginella bryopteris have been investigated for antiprotozoal activity using in vitro assays against Plasmodium falciparum, Leishmania donovani and Trypanosoma spp. Highest antiprotozoal activity was displayed by 7,4′,7″-tri-O-methylamentoflavone against the K1 strain with an IC50 of 0.26 μM and a cytotoxicity evaluated using L-6 cells of >160 μM, respectively.

Introduction

Infectious protozoal diseases such as malaria, leishmaniasis, human African trypanosomiasis and Chagas disease are major causes of morbidity and mortality in developing countries and the need for the discovery of antiprotozoal drugs is high. Acquired resistance leads to a loss of treatment capacity for currently available drugs (Wellems and Plowe, 2001). Previously, antiprotozoal and antimalarial activity for eight biflavonoids has been reported by Weniger et al. (2006) and others (Ichino et al., 2006, Azebaze et al., 2007). The heterosporous fern genus Selaginella is a rich source of biflavonoids (Sun et al., 1997, Silva et al., 1995, Lin et al., 2000, Chen et al., 2005). From the more than 60 species of Selaginella occurring in India, a few species are used medicinally, for example S. bryopteris (L.) Bak. as a tonic and for the regeneration of vitality (Dixit, 1982, Dixit, 1999). In a survey of Indian Selaginella species, extracts of S. bryopteris were screened against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum and IC50 values of eleven biflavone derivatives were determined.

The highest antiprotozoal activity was found for 7,4′,7″-tri-O-methylamentoflavone (11), a minor compound in S. bryopteris (Swamy et al., 2006). To study the in vivo activity of 11 in a Plasmodium berghei NMRI mouse model, we used a semisynthetic approach to convert amentoflavone (1) into a mixture of predominantly tri-O-methylated derivatives. This is the first report on in vivo data of antimalarial biflavonoids.

Section snippets

Results and discussion

From the S. bryopteris ethanolic extract, fractions of different polarity were obtained using toluene, EtOAc and n-BuOH for liquid–liquid partitioning. These were tested against T. b. rhodesiense STIB 900, T. cruzi Tulahuen strain C2C4, L. donovani strain MHOM-ET-67 and P. falciparum K1 (Table 1). The EtOAc fraction showed the highest activity and was further selected for the isolation of twelve pure compounds described in Swamy et al. (2006). The modest activity of the EtOAc fraction against

General experimental procedures

S. bryopteris (L.) Bak. was collected in December 2003 from Warangal, India. The plants were identified by Dr. V.S. Raju, Department of Botany, Kakatiya University, Warangal, India. Isolation and structural determination of the eleven biflavones from S. bryopteris is described in Swamy et al. (2006).

Derivatization

The O-methylation of amentoflavone was performed with trimethylsilyldiazomethane (TMSCHN2) (Presser and Hüfner, 2004, Aoyama and Terasawa, 1984). To a stirred solution of amentoflavone (100 mg, 0.186 

Acknowledgments

The authors thank Dr. V.S. Raju, Dept. of Botany, Kakatiya University, Warangal, India, for botanical identification of the plant material. This investigation received financial support from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). We also thank J.C. Janse, Leiden University, for providing the GFP-transfected P. berghei strain.

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