Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1970. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on September 18, 2007) Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 46-69).

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Orientador: Selma Giorgio / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T15:16:57Z (GMT). No. of bitstreams: 1 Barbosa_AdemarMesquita_M.pdf: 1384700 bytes, checksum: 2aee135192e2caab2d2eefed87104840 (MD5) Previous issue date: 2013 / Resumo: A leishmaniose tegumentar americana é uma doença causada pelos parasitas do gênero Leishmania e atualmente, está em franca expansão em todos os estados da federação. O tratamento é problemático, tendo em vista que os fármacos preconizados são de difícil administração e com sérios efeitos colaterais. Este trabalho foi realizado com o objetivo de testar compostos sintéticos, desenvolvidos pelo grupo de Química da USP/São Carlos. A avaliação de compostos com ação sobre enzimas do metabolismo foi realizada em formas promastigotas de Leishmania amazonensis e em cultura de macrófagos peritoneais murinos. Os resultados mostraram que dos 17 compostos testados, 3 (IDs 71S, 130S e 195 que são inibidores da enzima diidroorotato desidrogenase - DHODH) foram tóxicos para promastigotas de L. amazonensis-GFP, em ensaios de contagem em microscópio óptico e medição de fluorescência em espectro-fluorimêtro, apesar de que somente o ID 71S o ID 130S foram considerados significativos pela analise estatística. Esses inibidores reduziram a infecção com amastigotas em cultura de macrófagos peritoneais murinos, mas foram tóxicos para essas culturas de macrófagos. O composto ID 195 foi tóxico para os macrófagos nas concentrações mais altas. Em outro experimento demonstrou-se que em concentrações menores o ID 195 não foi tóxico para macrófagos, mas também não reduziu o numero de amastigotas no interior dos macrófagos / Abstract: Leishmaniasis is a disease caused by parasites of the genus Leishmania and currently is expanding in all states. Treatment is problematic, given that the recommended drugs are difficult to administer and serious side effects. The present study aims to test synthetic compounds, developed by the group of Chemistry, USP / São Carlos. The evaluation of compounds that act on enzymes of metabolism was performed in promastigotes of Leishmania amazonensis in cultured murine peritoneal macrophages. The results showed that the 17 compounds tested, three IDs (71S, 130S and 195 are dehydrogenase inhibitors enzima diidroorotato - DHODH) were toxic to promastigotes of L. amazonensis-GFP, in assays counting under a light microscope and measuring fluorescence spectra-fluorometer, though only the ID of the ID 71S 130S were considered significant by statistical analysis. These inhibitors are reduced infection with amastigotes in cultured murine macrophages peritoneias but these were toxic to macrophage cultures. The compound ID 195 was toxic to macrophages at the higher concentrations. In another experiment it was shown that at concentrations below 195 the ID was not toxic to macrophages, but did not reduce the number of amastigotes inside macrophages / Mestrado / Parasitologia / Mestre em Parasitologia

The application of Baylis-Hillman methodology has afforded access to a range of β-hydroxypropionate ester-AZT conjugates as potential dual-action HIV-1 IN/RT inhibitors. Two families comprising a total of nine β-hydroxypropionate ester-AZT conjugates were synthesised. The first family was accessed using O-benzylated salicylaldehydes and methyl acrylate and the second from unprotected salicylaldehydes using tert-butyl acrylate as the activated alkene. Spectroscopic methods were employed to fully characterize the compounds. Propargylation of the respective Baylis-Hillman adducts was achieved via conjugate addition of propargylamine. The resulting products were then employed in Cu(I)-catalysed “click” reactions with azidothymidine (AZT) to yield the desired β-hydroxypropionate ester-AZT conjugates. Exploratory studies were also conducted to access 4-hydroxycoumarins from Baylis-Hillman derived adducts and to construct customized chiral Baylis-Hillman reaction sites. Many 4- hydroxycoumarins are known to exhibit a wide range of biological activities, and extending Baylis-Hillman methodology to access these systems is an important challenge. Two approaches were investigated. The first involved the formation of a 4-phthalimidocoumarin, aromatisation and hydrolysis of which was expected to lead to the 4-hydroxycoumarin target. The second, a variation of the first, involved the use of 4-(chrolomethyl)coumarin intermediates. Unfortunately, while various intermediates were prepared and characterised, neither approach led ultimately to the desired targets. N-substituted borneol-10-sulfonamides were constructed from camphor-10- sulfonyl chloride as chiral Baylis-Hillman reaction sites. In a preliminary study, however, none of the N-substituted borneol-10-sulfonamides exhibited Baylis-Hillman catalytic activity.

This project has been concerned with the application of the Baylis-Hillman methodology to the synthesis of medicinally important diketo acid analogues (cinnamate ester-AZT conjugates and 3-hydroxy ester-AZT conjugates) as dual-action HIV-1 IN/RT inhibitors; and on exploratory studies in the preparation of 3-(amidomethyl)-(1H)-2-quinolones as PR inhibitors; and (1H)-2- quinolone-AZT conjugates as dual action IN/RT inhibitors. A series of Baylis-Hillman adducts has been prepared, typically in moderate to excellent yield, by reacting 2-nitrobenzaldehyde with methyl acrylate, ethyl acrylate and methyl vinyl ketone in the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO). Subsequently, various transformations that include conjugate addition of primary and secondary amines to the α,ß-unsaturated moiety to obtain 2- (aminomethyl)-3-hydroxy-3-(2-nitrophenyl)propanoate derivatives, effective SN2´ substitution of the BH ß-hydroxy by a Vilsmeier-Haack in situ-generated chloride to afford Baylis-Hillman allyl chlorides, iron in acetic acid-catalyzed cyclisation to 3-acetoxymethyl-(1H)-2-quinolone derivatives were achieved. Thus, using the Baylis-Hillman methodology, two nuanced classes of diketo acid analogues were constructed. These involved conjugating appropriate propargylamine derivatives with AZT using the „click‟ reaction. In an exploratory study, the quinolone derivative, precisely 3-acetoxymethyl- (1H)-quinol-2-one, was transformed into 3-hydroxymethyl-(1H)-quinol-2-one using potassium carbonate in a mixture of methanol and water (1:1). Following successful hydrolysis, the resulting alcohol was transformed to the corresponding chloride, 3-chloromethyl-(1H)-quinol-2- one, using thionyl chloride. Subsequent nucleophilic substitution afforded 3-(aminomethyl)- (1H)-2-quinolone derivatives which were subsequently transformed to 3-(amidomethyl)-(1H)-2- quinolones; and 3-[(propargylamino)-methyl]-(1H)-quinol-2-one as precursors to quinolone- AZT derivatives. All compounds were characterized by NMR, IR, and where appropriate, high resolution MS

Laboratory and greenhouse experiments were conducted to evaluate the allelopathic effects of the extracts and residue Arctotis arctotoides (L.f.) O. Hoffm on selected vegetable crops. The study aimed to address the following specific objectives to (i) examine the ultra structures of the leaf of A. arctotoides using the Scanning Electron Microscope (SEM), (ii) carry out comprehensive qualitative and quantitative phytochemical analysis of the root and shoot materials of the plant, (iii) investigate the allelopathic activities of the root and shoot aqueous extracts of A. arctotoides at concentrations of 10, 8, 6, 4 and 2 mg/ml on germination, radicle and plumule growth of cabbage, carrot, tomato and spinach, (iv) evaluate the inhibitory effects of the dried shoot residue of the plant at 10, 20 and 40 g kg-3 of soil (treatments B, C and D) and the control (treatment A) on the morphology, growth and chlorophyll pigment content of tomato and cabbage transplants at 1, 2, 3 and 4 weeks after transplanting and (v) assess the effects of the dried shoot residue of A. arctotoides on the yield, nutrient uptake by the leaves of tomato and cabbage at 4 and 12 weeks after transplanting. Finally, to analyze the residual mineral content of the soils with tomato and cabbage transplants at 12 weeks after transplanting. The the SEM revealed that anisocytic stomata and glandular trichomes (GTs) were numerous on the abaxial than the adaxial surfaces of A. arctotoides. The non glandular trichomes (NGTs) were also present on both surfaces but lesser on the abaxial. Morphologically, the GTs were peltate, uniseriate and globular head while the NGTs were cylindrical and filamentous with variable number of cells at the basal portion. The energy dispersive X-ray spectroscopy of some crystals showed that Na+ Mg2+ and Ca2+ were the major constituents of the crystal deposit found around the GTs and stomata. The results of the phytochemical composition of the root and shoot extracts of A. arctotoides confirmed the occurrence of alkaloids, flavonoids, phenolics, saponnins, tannins and triterpenes as the common constituents. In addition, cardiac glycosides and steroids were also detected in the shoot of the A. arctotoides. Quantitative estimation of the chemical constituents of the crude extracts further revealed that the alkaloid content in the root higher (0.97 percent) than the shoot (0.64 percent). The quantity of flavonoids detected in the shoot (1.02 percent) was more than that observed in the root (0.35 percent). Others (phenolics and tannins) were marginal in the two plant parts. The results of the inhibitory effects of the root and shoot aqueous extract at the varying concentrations showed that root extract at 10 mg/ml considerably reduced the germination of cabbage, carrot, tomato and spinach seeds by 84.0, 83.2, 72.8 and 37.4 percent respectively. Incubation of the shoot extract at the same concentration resulted in 100 percent inhibition of cabbage and carrot seed germination whereas those of tomato and spinach were suppressed by 91.5 and 61.2 percent respectively. The two extracts at the varying concentrations also had a significant reduction on the radicle and plumule growth of the four vegetables. Addition of the shoot residue to the soil showed massive chlorosis, necrotic lesions and wilting of tomato and cabbage leaves under treatments C and D at 2 weeks after transplanting. The number of leaves, leaf area, dry shoot and root weight of the two vegetables grown in the amended soils were also drastically reduced. The inhibition percentages due to the addition of the three concentrations of A. arctotoides dried shoot residue on the dry shoot weight at 4 weeks after transplanting were 38.6, 45.5 and 70.3. for tomato and 57.5, 73.3 and 87.5 percent for cabbage. Similarly, the declines in the dry root weight of 61.3, 82.9.4 and 83.4 percent for tomato as well as 53.1, 54.7 and 67.2 percent for cabbages were recorded for the two vegetables under treatment B, C and D during the period. The results further showed that the dry fruit yield and shoot weight of tomato under the treatments B, C and D decreased with increase in shoot residue concentrations of A. arctotoides. Relative to treatment A, no significant differences were recorded in the dry head weight of cabbage under the residue treated groups. The reductions in the fruit yield and fresh head weight caused by treatments C and D were 37.2 and 84.8 percent for tomato and 30.9 and 72.4 percent for cabbage. The findings on the mineral contents in the leaves of the two vegetables revealed significant differences in the uptake of N, Mg, Na, Cu and Fe by tomato leaves. The concentrations of N, K, Na and Zn in cabbage leaves also differed. However, the P content was relatively constant in the leaves of the two vegetables at 4 and 12 weeks after transplanting. At 12 weeks after transplanting, the Fe content in soils with tomato and cabbage treatments C and D was greatly enhanced in comparison with the other nutrients. The residual N, P and Zn detected in soils planted to cabbage were similarly equal among all the groups including the control. Thus, under the greenhouse experiment, Arctotis arctotoides (L.f) O. Hoffm has been shown to contain some phytotoxic chemical compounds in its root and shoot materials. The compounds either singly or collectively have demonstrated some inhibitory potentials on the germination, growth and yields of cabbage, carrot, tomato and spinach evaluated in this study.