Phytochemical Investigation of Turraea Robusta, Turraea Nilotica and Ekebergia Capensis for Antiplasmodial and Cytotoxic Compounds

ABSTRACT

In an effort to identify antiplasmodial and/or cytotoxic secondary metabolites, three African medicinal plants, Ekebergia capensis, Turraea nilotica and Turraea robusta were investigated for antiplasmodial and cytotoxic compounds. Except for T. nilotica, the other plants were selected on the basis of previous reports on antiplasmodial activities of crude extracts. A combination of different chromatographic techniques including preparative HPLC was employed in isolation of compounds. The characterization of compounds was done using 1D and 2D NMR as well as MS analyses. The crude extracts and the isolated compounds were evaluated for antiplasmodial activity against the chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum using a semiautomated micro dilution technique which measures the ability of the compounds to inhibit the incorporation of (G-3H) hypoxanthine into the malaria parasite. They were also evaluated for cytotoxicity properties against African green monkey kidney (vero), using a rapid colourimetric assay that employs 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as a viability indicator. Selectivity index (SI) defined as IC50 (Vero cells) / IC50 (P. falciparum) was also determined.

 A total of twenty six compounds were isolated. From the stem bark of Turraea robusta seven compounds were isolated of which acetoxy-7-deacetylazadirone (28) and 11-epi-toonacilin (62) were new to the species whereas azadironolide (192) was new to the genus. Turraea nilotica leaves, root and stem bark yielded twelve compounds of which five [mzikonone (17), azadirone (19), acetoxy-7-deacetylazadirone (28), 1α,3α-diaacety-7α-tigloylvilasinin (40) and hipidol B (96)] were new to the species and four [toonapubesins (194) and phytosterols (195-197)] were new to the genus. From the root bark and leaves of Ekebergia capensis ten compounds were isolated with two glycoflavonoids (199-200) being new to the genus and a new natural product, 3-oxo-12β-hydroxy-oleanan-28,13β-olide (198).  

Azadironolide (192) displayed the highest antiplasmodial activity with an IC50 of 1.1 and 2.4 μM against W2 and D6 strains respectively, with a SI > 10.5. This compound can be evaluated further for its antimalarial activity in a mouse model. The rest of the compounds displayed moderate to low antiplasmodial activities with IC50 ranging 14.4-205 μM against the two P. falciparum strains with low selectivity index (< 10). The low SI values indicate that the observed moderate antiplasmodial activity may be due to general cytotoxicity rather than the activity against the parasites. This motivated further cytotoxicity investigation on cancerous cell lines, mouse breast cancer (4T1), human larynx carcinoma (HEp2) and human breast cancer (MDA-MB-231). Six compounds were cytotoxic to cell lines 4T1 and HEp2 (IC50 < 20 μM) with oleanonic acid (160) being the most cytotoxic to HEp2 cell line with an IC50 value of 1.4 μM. 

 

Interaction of oleanonic acid (160) isolated as a major compound from E. capensis, with  five triterpenoids; 2,3,22,23-tetrahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18- tetracosatetraene (151),  2-hydroxymethyl-2,3,22,23-tetrahydroxy-6,10,15,19,23-pentamethyl-6,10,14,18 tetracosatetraene   (152), ekeberin A (158), oleanolic acid (159) and 3-epi-oleanolic acid (161) was evaluated against vero and HEp2 cell lines. No appreciable synergism was observed.

Structure-Activity–Evaluation by acetylating niloticin (25), piscidinol A (27) and oleanolic acid (159) was carried out. The derivatives were evaluated for cytotoxicity activity where niloticin acetate (201) and piscidinol A diacetate (203) were of lower activity than the parent molecules while oleanolic acid acetate (202) was seven folds more active than oleanolic acid.

 

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