Corona, Maria del Rayo Camacho; (1998) Natural products against protozoal diseases. Doctoral thesis (Ph.D), UCL (University College London).

Text Natural_products_against_proto.pdf Download (28MB)

Abstract

Disease caused by parasite protozoa, including malaria, leishmaniasis and trypanosomiasis, result in considerable mortality and morbidity throughout the world. There is an urgent need for new chemotherapeutic drugs for the treatment of these diseases. Natural products represent one source of novel antiprotozoal drugs. Forty-seven plant species obtained from Ghana, Panama, Mexico, Oman, Egypt and Kew Gardens, London were selected for antiprotozoal screening either because of their traditional use or because of chemotaxonomic considerations. Methanolic and aqueous extracts of these plants were prepared and screened against L. donovani promastigotes and T. b. brucei trypomastigotes in vitro. The cytotoxicity of the extracts was determined against KB cells and compared with their antiprotozoal activities in vitro. The toxicity of selected extracts was also assessed using P388D1 cells and brine shrimps. From the preliminary screening Celaenodendron mexicanum, Galphimia glauca, Guarea rhopalocarpa, Stephania dinklagei, Triclisia patens, Cephaelis camponutans and Hintonia latiflora were selected for further investigation in order to isolate their active principles. Bioactive-guided fractionation using Z. promastigotes, P. falciparum, KB cells or brine shrimps in vitro, and a combination of chromatographic techniques yielded some 38 pure compounds of which 11 were novel, and 9 semisynthetic derivates were prepared. The structure of isolated compounds was determined by UV, IR, HRMS, 'H NMR, "C NMR, COSY-45, HMQC, HMBC, COLOC and NOESY experiments. C. mexicanum yielded 3 active terpenes, epi-oleanolic acid, 3α-hydroxy-tirucalla-7,24Zdien-26 oic acid and 3-oxo-tirucalla-7,24Z-dien-26 oic acid. In addition, 4 terpenes, friedelin, maytensifolin B, 3β-hydroxy-friedelan-16-one and celaenodendrolide as well as 3 biflavonoids, amentoflavone, podocarpusflavone A and podocarpusflavone B were also isolated from this plant. G. glauca afforded the active flavonol quercetin and the novel terpenes galphimine C, galphimine D, galphimine E and glaucamine, and the known steroids stigmasterol and sitosteryl-3-O-β-D-glucopyranoside. G. rhopalocarpa yielded 4 new active terpenes, 23-hydroxy-5α-lanosta-7,9(11),24EZtriene-3-one, lanosta-7,9(l l),24EZ-triene-3α,23-diol, ent-8(14), 15-sandaracopimaradiene- 2β,18-diol, and ent-8(14),15-sandaracopimaradiene-2α,18-diol, together with the coumarin scopoletin. S. dinklagei afforded 6 aporphine alkaloids, the novel stepharandine, Nmethyl-liriodendronine and 2-0,N-dimethyl-liriodendronine and the known corydine, liriodenine and dicentrinone, and the anthraquinone aloe-emodin. T. patens yielded 2 active principles the bisbenzylisoquinoline alkaloids phaeanthine and aromoline. Two active quinones, benzo[g]isoquinoline-5,10-dione and 1-hydroxybenzoisochromanquinone were isolated as the active principles of C camponuntants. Two phenylcoumarins 5-0-β-D-glucopyranosyl-3',4'dihydroxy-7-methoxy-4-phenylcoumarin, 5-0-β-D - galactopyranosyl-3',4'dihydroxy-7-methoxy-4-phenylcoumarin; one cucurbitacin, 3-0-β-D-glucopyranosyl-23,24-dihydrocucurbitacin F and one flavonoid, 7-methyl-luteolin were isolated H.latiflora. A total of 97 natural products including alkaloids, quinones, terpenes, flavonoids and coumarins, were screened for their antiprotozoal activity L.donovani, T.b.brucei and cytotoxicity against KB and P388D1 cells in vitro, in order to establish structure activity relationships. This study revealed that the most active compounds were the bisbenzylisoquinoline alkaloids phaeanthine and fangchinoline with IC50 values at 1.5 µg/ml and 0.24 µg/ml respectively against promastigotes forms of L.donovani. The most active against T.b.brucei and T.cruzi was the quinone 1-acetyl-benzoisochromanquinone with IC50 values of 0.17 and 1.79 µg/ml, respectively. 7-Methyl-luteolin and quercetin were the most active d.gànsXP.falciparum with IC50 values of 13.9 and 6.5 µg/ml respectively. Acetylstrictodine and acetylstrictosidine lactam gave a 30 and 33.2% of inhibition of liver parasites in experimental model of L.donovani compared to pentostam. Selected natural products and crude extracts were assessed for their immunomodulatory activity in vitro using the mitogenesis of BALB/c mice spleen cells and superoxide release in murine macrophages cell line J774. In combination with Con A, the strongest synergistic effect on lymphocyte proliferation was observed with 6 compounds, having a maximum effects in the interval of 4-5 times over control at concentration range of 0.001-1 µg/ml. In the case of superoxide release, 31 compounds were able to promote spontaneous release of superoxide in the range of 2-6 times over control at concentrations equal or lower than 1 µg/ml.

Download activity - last month

Export as JSONCSVXML

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item