Antiplasmodial activities of limonoids from Entandrophragma angolense ( Meliaceae ), and their semi-synthetic derivatives: Study of the structure-activity relationship.

Abstract

SUMMARY AIM: In the aim to understand the structure-activity relationship of some natural antimalarial agents, two limonoids 7α- acetoxydihydronomilin 1 and 7α- obacunyl acetate 2 obtained from E. angolense and two new semi-synthesized limonoids 7α- acetoxy-14, 15-deepoxynomilin 3 and 1, 2- dihydro-1, 4-dihydroxy-6-deoxoatalantin 4 obtained by partial synthesis from 7α- acetoxydihydronomilin 1 were evaluated for their in vitro activity against the W2 strain of Plasmodium falciparum . METHODS: 7α- acetoxydihydronomilin 1 and 7α- obacunyl acetate 2 were obtained after chromatographic separations of the plant extract on silica gel columns. 7α- acetoxy-14, 15-deepoxynomilin 3 was obtained by reduction of 7α- acetoxydihydronomilin 1 with zinc-copper couple and 1,2-dihydro-1,4-dihydroxy-6-deoxoatalantin 4 was obtained by hydrolysis of 7α- acetoxydihydronomilin 1 with a KOH solution. The structural determinations of the compounds were made through NMR (Nuclear Magnetic Resonance) spectroscopy analysis. To assess antimalarial activities, different dilutions of the compounds were incubated at 37°C with cultured W2-strain of P. falciparum parasites for 48 hours. Parasites were thereafter fixed and stained, and parasitemias of treated and control cultures were determined. Results were means, compared to untreated controls, from 3 experiments. RESULTS: 7α- obacunyl acetate 2 was found to be the most active in vitro against P. falciparum parasites, with an IC 50 of. 5.14 µM. 7α-acetoxydihydronomilin 1 , 7α- acetoxy-14, 15-deepoxynomilin 3 and 1, 2- dihydro-1, 4-dihydroxy-6-deoxoatalantin 4 were found to be less active. CONCLUSION: Although the presence of α,β–unsaturated ketone is an important feature for enhanced antiplasmodial activity of limonoids, the localisation of α,β–unsaturated carbonyl moiety in ring A seems to be critical for the enhancement of that activity.