Paine, Angela; (1996) Plants as sources of anti-protozoal compounds. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The majority of the world's population relies on traditional medicine, mainly plant-based, for the treatment of disease. This study focuses on plant remedies used to treat tropical diseases caused by protozoan parasites. The following protozoal diseases: African trypanosomiasis, leishmaniasis. South American trypanosomiasis and malaria, and the traditional use of plant remedies in their treatment, are reviewed in a world wide context. In the present work, vector and mammalian forms of Trypanosoma b. brucei, the vector forms of Leishmania donovani and Trypanosoma cruzi and the mammalian forms of Plasmodium falciparum were maintained in culture in vitro in order to evaluate the activity of a series of plant extracts, pure natural products and synthetic analogues against these protozoan parasites in vitro. Six species of West African plants, Alstonia boonei, Alchornea cordifolia, Annona senegalensis, Lonchocarpus cyanensis, Tamarindus indica and Ximenia americana, reputated to be used in the treatment of human African trypanosomiasis, were evaluated for activity against T. b. brucei, L. donovani and T. cruzi, in vitro. Crude extracts of three of these plants, A. boonei, A. cordifolia and A. senegalensis, were active in the range of 30 - 500 μg/ml against T. b. brucei but inactive against T. cruzi and L. donovani. A. boonei was further investigated, resulting in the isolation of the indole alkaloids, echitamine, undulifoline, 12-methoxyechitmidine and a mixture of echitamidine and 12-methoxyechitamidine. These were identified on the basis of UV, MS, 1H NMR, 13C NMR and COSY spectroscopy. 12-methoxy-echitamidine and undulifoline have not previously been reported to have been isolated from A. boonei. Four mixtures of terpenoids were also isolated from A. boonei. The indole alkaloids caused a 100% inhibition of T. b. brucei mammalian forms at a concentration of 30μg/ml in vitro and three of the mixtures of terpenoids inhibited the motility of T. b. brucei procyclic forms in a range of concentrations from 60-250μg/ml in vitro. Lignans representing the natural product surinamensin, from Virola surinamensis and a lignan from Virola pavonis from Brazil, together with twenty four synthetic analogues, were tested for activity against L. donovani promastigote and amastigote forms in vitro. Fourteen lignans, including surinamensin and the natural lignan from V. pavonis, supressed promastigote forms 100% at a range of concentrations from 30-100 μM, but ten of them were toxic to macrophages in the amastigote form test. Four synthetic lignan analogues with sulphur bridges between C-8 and C-4' were selectively active against L. donovani amastigotes at 30 and 100 μM and one of these (3,4 - dimethoxyphenyl -(l-(4- methylphenyl)thio)ethyl ketone) had a 42% inhibition in vivo at a dose of 100 mg/kg/day in the 5 day suppressive test in mice. Mode of action studies suggested that these lignans may inhibit microtubule formation or function. The lignan podophyllotoxin, the alkaloids, camptothecin and ellipticine and the flavonoids, morin, phloridzin, phloretin and cosmetin and the phenolic compound, maclurin were tested against L. donovani amastigote forms in vitro. None of these compounds showed any selectivity in their action against L. donovani amastigotes in the mouse peritoneal macrophage test. A traditional anti -leishmanial treatment from Iraq, known as Kubbal Azrak, was investigated for anti-Leishmania spp. activity and had ED50 values of 0.05 and 0.01 μg/ml against L. donovani amastigote and promastigote forms in vitro but proved toxic to macrophages. When tested against Leishmania major in vivo it was inactive. The major component of Kubbal Azrak was identified as gentian violet, on the basis of thin layer chromatography, UV, 1H NMR and 13C NMR spectroscopy. Cryptolepis sanguinolenta is traditionally used as an anti- malarial remedy in Ghana and the major alkaloid, cryptolepine had an IC50 value of 0.134μM against P. falciparum in vitro, comparable to chloroquine which has an IC50 value of 0.023μM. Cryptolepine was not active against P. berghei in vivo in mice. UV spectroscopy was used to iv indicate that cryptolepine interacts with DNA.

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