Chemical constituents and antiplasmodial activity of Dacryodes edulis (G.Don) H.J.Lam (Burseraceae) and Celtis adolphi-friderici Engl. (Cannabaceae)

Abstract

Pending the development of an effective vaccine for everyone, antimalarials remain the only way to fight against the mortality and morbidity generated by parasites. Despite the antimalarial arsenal currently on the market, the problems of parasite resistance to drugs make research and development of new active ingredients permanent. Previous research has shown that medicinal plants are an important source of active ingredients. These active ingredients in their different forms (extracts, fractions, pure compounds) could be used to justify the use of the plants from which they are derived in traditional pharmacopoeia or to suggest other valuation axes. They could also be used as a raw material for the development of phytomedicines or in the case of isolated pure compounds, as candidates for drug development or as a source of inspiration for their designs. It is in this spirit that, within the framework of this thesis, we undertook the chemical study and the evaluation of the antiplasmodial activity of two Cameroonian medicinal plants: D. edulis (G. Don) HJ Lam (Burseraceae) and C.adolphi- friderici Engl (Cannabaceae). D. edulis is used in traditional medicine to treat fever, headache, malaria, while C. adolphi-friderici is used to treat cough, fever, headache, tuberculosis and eye pain. The study of the different parts of these two plants by liquid-liquid, solid-liquid partition and column chromatography has led to the isolation of thirty-one compounds, including a new cerebroside. Structural elucidation was performed mainly by high resolution mass spectrometry and nuclear magnetic resonance spectroscopy 1D (1H and 13C) and 2D (COSY, HMQC, HSQC, HMBC and NOESY). The isolated compounds were grouped into different classes including 1 cerebroside, 5 triterpenoids, 2 steroids, 2 xanthones, 3 derivatives of ellagic acid, 1 depside, 2 dicarboxylic acids, 6 phenolic compounds (including 3 phenolic amides), 1 auranthiamide acetate, 2 triglyceryls, 2 fatty acids, 1 gallic acid derivative, 1 indole alkaloid, 1 carbamide, 1 amino acid. From the stem bark of D. edulis, lichexanthone, griseoxanthone C, 3,3'-di-O-methylellagic acid, 3,3',4-tri-O-methylellagic acid, 3,3′′-di-O-methylellagic 4-O-(3′′-galloyl)-β-D-xylopyranoside acid, 3,4-dihydroxybenzoic, confluentic acid, 3-oxo-lanosta-7,24-Z-dien-26-oic, β-amyrin, β-amyrin acetate, and the mixture of β- and α-amyrin were isolated. In addition, ethyl gallate, auranthiamide acetate, glyceryl-1-tetracosanoate, mixture of β-sitosterol and stigmasterol, β-sitosterol-3-O-β-D-glucopyranoside were isolated from the leaves of D. edulis. A new cerebroside: eloundemnoside and fourteen known compounds including vanillin, hydroxybenzoic acid, allantoin, azelaic acid, sebacic acid, trans-N-feruloyloctopamine, trans-N-feruloyltyramine, trans-N-coumaroyltyramine, friedeline, glycerol 1-octadecanoate, indole 3-carboxaldehyde, aspartic acid, heptacosanoic Doctorat/PhD thesis written and presented by DONGMO JUMETA Johane Kevine acid and laceroid acid have been isolated from the roots of C. adolphi-friderici. It is important to note that all compounds except steroids were isolated from D. edulis for the first time. Likewise, the compounds isolated from C. adolphi-friderici are obtained for the first time from this species. In addition, lichexanthone, griseoxanthone C, confluentic acid, auranthiamide acetate , glyceryl-1-tetracosanoate and 3,3′′-di-O-methylellagic 4-O-(3′′-galloyl)-β-D-xylopyranoside acid were isolated for the first time from the Burseraceae family. The crude extracts, the fractions and some isolated compounds were tested on the 3D7 sensitive strains and the Dd2 multiresistant strains to chloroquine of P. falciparum (using the protocol described by Smilkstein and collaborators in 2004). The methanolic extract of the stems bark of D. edulis showed moderate antiplasmodial activity with IC50 values of 9.62 and 6.32 μg/mL, respectively, on Pf3D7 and PfDd2, while the hydroethanolic leaves extract of D. edulis showed good antiplasmodial activity with IC50 values of 3.10 and 3.56 μg / mL, respectively, on the two strains. The EtOAc fraction of the methanolic extract of the stem bark of D. edulis showed the best activity (IC50 = 1.44 μg/mL) and led to the isolation of the most active compound: 3,3′,4-tri-O-methylellagic acid (IC50 = 0.63 μg/mL on the Dd2 strain). The hexane fraction of the hydroethanolic leaves extract of D. edulis also showed good activity (IC50 = 2.70; 2.98 μg/mL on 3D7 and Dd2 strains, respectively). The purification of the EtOAc fraction of the hydroethanolic leaves extract of D. edulis led to the isolation of ethyl gallate which exhibited an interesting antiplasmodial activity with IC50 values of 1.15 and 2.86 μg/mL on Dd2 and 3D7 strains, respectively. The acetone extract of C. adolphi-friderici roots showed good antiplasmodial activity on Pf3D7 and PfDd2 with IC50 values of 6.91 and 6.03 μg/mL, respectively. Trans-N-feruloyltyramine from C. adolphi-friderici showed antiplasmodial activity with an IC50 of 23.53 and 18.43 μg/mL, respectively on Pf3D7 and PfDd2 the strains. An acute oral toxicity study of the aqueous extract of the leaves of D. edulis was carried out in order to verify its safety. The extract was found to be no toxic. The results obtained in the study of these two plants constitute evidence to justify their use in the traditional pharmacopoeia for the treatment of malaria. The preformulation of an antimalarial syrup was carried out on the basis of the results obtained.