From structural studies of natural products to the discovery of a selective antiplasmodial derivative: a serendipity story

In our continuing effort directed to the search for new antiplasmodial natural compounds from plants of the tropical biodiversity, the phytochemical study of Canthium majus Drake, a Madagascan plant belonging to the family Rubiaceae, was carried out. Bioguided fractionation of the ethyl acetate leaf extract led to the isolation of eight new diarylheptanoid glucosides together with the known β-sitosterol, which showed a weak antiplasmodial activity due to a possible stomatocytogenic[1] effect. The structures of the diarylheptanoid glucosides were similar to those isolated from the rhizomes of Tacca chantrieri André by Yokosuka and co-workers[2].

After chemical modifications of the natural glucosides, including hydrolytic cleavage, methylation and esterification, the determination of their absolute configuration using the CD exciton chirality method [3] applied to acyclic 1,3 dibenzoates [4] systems has been successfully achieved.

Naturally-occuring diarylheptanoid glucosides and their derivatives were evaluated, in vitro, for their antiparasitic activity against Plasmodium falciparum (FcB1), Leishmania donovani (amastigote and promastigote forms) and Trypanosoma brucei as well as for their cytotoxic activity against HL-60, KB and MRC5 cell lines. Among 17 compounds investigated, one diarylheptanoid exhibited a selective antiplasmodial activity and no cytotoxicity.

Acknowledgement: This works was supported by an ICSN-CNRS grant to one of us (M.A B.).

We express our thanks to G. Aubert for the cytotoxicity assay, Pr. P. Loiseau and Pr. C. Bories for the antileishmanial and antitrypanosomal assay.

References: 1. Ziegler H L et al. (2002) Antimicrob Agents Chemother 46: 1441.

2. Yokosuka A et al. (2002)J Nat Prod 65: 283.

3. Harada N et al. (1972) Acc Chem Res 5: 257.

4. Harada N et al. (1991)J Am Chem Soc 113: 3842.