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A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg,in fulfillment of the requirements for the degree of Master of Science in Medicine. Johannesburg, South Africa, 2015 / Plasmodium falciparum remains the most virulent cause of malaria. With increasing drug resistance to artemisinin and other antimalarial drugs, combined with an absence of an effective vaccine, there’s a critical need for new agents to complement existing treatment and prophylaxis. Therefore, the aim of the study was to evaluate the in vitro antimalarial activity and potential toxicity to mammalian cells of select synthetic and natural colourants, nucleoside and imidazo[1,2a]pyridine (IP) analogues on the erythrocytic stages of the 3D7 chloroquine-sensitive strain of P. falciparum. The P. falciparum 3D7 strain was maintained in vitro according to standard methods. Quinine and chloroquine were used as positive controls. The tritiated hypoxanthine incorporation assay was used for evaluating the ability of test compounds to inhibit the growth of P. falciparum. Active test compounds were tested in combination studies with quinine. Uninfected human red blood cell (RBC) toxicity was analysed spectrophotometrically. The ability of test compounds to inhibit -haematin formation, a metabolic pathway that sequesters toxic haem within the parasites, was determined. Cytotoxic activity of active compounds was evaluated on two human cell lines (HEK293 and K562) using the [3H]-thymidine incorporation assay. Data was analysed using the one-way ANOVA test and reported as the mean ± standard deviation of at least triplicate experiments and significant difference when p < 0.05. Of the 56 compounds tested, the synthetic colourants showed the most potent antimalarial activity. Methylene blue and safranin O were most potent with IC50 values of 4.19 ± 0.16 nM and 86.50 ± 2.61 nM, respectively, compared to quinine (IC50: 103.90 ± 8.30 nM), and displayed negligible toxicity to uninfected human RBCs. Combination studies with methylene blue and quinine demonstrated a synergistic interaction. Methylene blue also demonstrated the highest selectivity indices (480 and 968) compared to quine (180). Curcumin (diferuloylmethane), a natural extract was active (IC50: 2.29 ± 0.18 μg/ml) against P. falciparum, but significantly (p < 0.05) less potent than quinine. Curcumin was 78-fold more active in inhibiting -haematin formation than quinine, indicating of a possible mechanism of action. The most active nucleoside analogue, JLP118.1 (IC50: 1.79 ± 0.12 μM), demonstrated inhibitory activity against the trophozoite stage of P. falciparum. The imidazopyridine analogue, IP-4, displayed the least potent antimalarial activity (IC50: 15.3 ± 0.41 μM) of the synthetic compounds tested, with low selectivity indices < 1. The study has confirmed the potent antimalarial activity and relative safety of methylene blue as well as its potential as an antimalarial drug. The nucleoside and imidazopyridine analogues showed promising activity and with structural modification their potency and selectivity indices may be enhanced.

African trypanosomiasis is a protozoan infection affecting tens of thousands of people and millions of livestock animals across sub-Saharan Africa. In humans the disease is fatal without chemotherapeutic intervention and in animals it causes a severe anaemia that greatly impairs productivity. Available drug compounds are difficult to administer and unacceptably toxic. A natural product, ascofuranone, inhibits a key trypanosome specific respiratory enzyme, trypanosome alternative oxidase, and was shown over a decade ago to be trypanocidal using both in vitro and in vivo experiments. The compound suffers from rapid metabolism and contains several functionalities undesirable in a drug compound. Despite the promising activity the lack of applicable synthetic methods available hampered the development of chemotherapeutics from ascofuranone. In this work, novel synthetic routes were completed to explore the lead compound. New synthetic methods were successfully developed using palladium catalysed Suzuki couplings and Lewis acid catalysed rearrangements. Ortho-lithiation approaches also afforded potent novel inhibitors. Of particular note is a benzisoxazole, which is expected to alleviate many of the metabolic issues associated with ascofuranone. Alternate heterocycle analogues were explored and an interesting indazole analogue obtained. Finally, chemical methods were developed towards the benzisoxazole and indazole motifs with carboxylic acids, amenable to diversification by amide coupling. A preliminary range of novel amide containing 5, 6-heterocycles were synthesized to begin SAR exploration of these structures.

Call number: LD2668 .T4 1985 M33 / Master of Science

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Made available in DSpace on 2014-06-11T19:30:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-10Bitstream added on 2014-06-13T21:01:40Z : No. of bitstreams: 1 avila_rw_dr_botib.pdf: 773594 bytes, checksum: 91593c7be9e57a5cf5d522fe8657b502 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O Brasil detém uma das maiores diversidades de lagartos do mundo, com 13 famílias e 236 espécies. Embora várias espécies do território brasileiro tenham sido investigadas nos últimos anos quanto a aspectos de história natural, o conhecimento acerca do parasitismo ainda é escasso concentrado em alguns ecossistemas, como Restingas e Floresta Atlântica. No presente trabalho, a presença de helmintos foi avaliada em diversas espécies de lagartos de três ecossistemas do Brasil Central: Cerrado, Pantanal e Amazônia. Os espécimes utilizados foram provenientes de cinco coleções científicas: Coleção de Vertebrados da Universidade Federal de Mato Grosso, Coleção de Herpetologia da Universidade Federal de Góias, Coleção Zoológica de Referência do Campus de Corumbá, Coleção Zoológica de Referência da Universidade Federal de Mato Grosso do Sul e Coleção Herpetológica Arlindo de Figueiredo Bedá. Após a necropsia, os helmintos foram identificados e depositados na Coleção Helmintológica do Instituto de Biociências da UNESP de Botucatu. Foram calculados os seguintes parâmetros de infecção: Prevalência (porcentagem de indivíduos infectados em cada espécie hospedeira) e a Intensidade média da infecção (número médio de parasitos nos lagartos infectados). 0 índice de diversidade de Brillouin foi calculado para cada espécie hospedeira. Relação entre o comprimento rostro-cloacal e número total de parasitas e diversidade de helmintos foi testada através de correlação de Pearson. Análises de agrupamento (UPGMA) foram realizadas para avaliar a similaridade (índice de Sorensen) entre as áreas dentro dos biomas utilizando apenas os dados qualitativos. Um total de 955 indivíduos pertencentes a 66 espécies de lagartos foram necropsiados, dos quais 45,8% estavam parasitados. A prevalência por ecossistema foi de 58% de animais parasitados na amostra do Cerrado... / Brazilian diversity of lizards includes 236 species, although many aspects of lizard biology, including parasitism are poorly studied. These few studies are concentrated mostly on animals from Atlantic forest and Restinga. Herein we investigate the helminth parasites of lizards in three biomes of central Brazil Cerrado (savanna-like vegetation), Pantanal (floodplain) and Amazonia (rain forest). We look for helminths within the body cavity, esophagus, stomach, lungs, small and large intestines of each specimen under a stereomicroscope. Nematodes were cleared in phenol; Cestoda, Trematoda and Acanthocephala were stained in Carmim, dehydrated graded alcohols, cleared in Creosote and after identification, these helminths were deposited in the Coleção Helmintológica do Instituto de Biociências da Unesp de Botucatu, Brazil. A total of 955 individuals from 66 species of lizards representing 9 families were assessed, wherein 45.8% displayed helminthes. In the Cerrado the prevalence was 58% (a total of 436 specimens from 39 species), whereas in the Pantanal the overall prevalence was 53.9% (221 individuals from 27 species) and 54.2% (295 specimens from 31 species) was the prevalence in the Amazon. A total of 156,435 helminths from 62 species, including 8 trematodes, 2 acanthocephalans, 5 cestodes and 47 nematodes were found. Tropiduridae, Teiidae an Scincidae were the most parasitized lizard families in all biomes, while Gymnophthalmidae were lesser infected. Lizards with larger body sizes tend to have richer diversity and abundance of helminths. Cluster analysis revealed higher similarities between different populations of the same lizard species than phylogenetically closest sympatric species

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Includes bibliography / 118, [78] leaves, [1] leaf of plates : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1984

Thesis (Ph.D.) - University of Glasgow, 2008. / Ph.D. thesis submitted to the Faculty of Biomedical and Life Sciences, Division of Immunology, Infection & Inflammation, University of Glasgow, 2007. Includes bibliographical references. Print version also available.