This study has involved the design, synthesis and evaluation of novel HIV-1 enzyme inhibitors accessed by synthetic elaboration of Baylis-Hillman adducts. Several series of complex coumarin-AZT and cinnamate ester-AZT conjugates have been prepared, in high yields, by exploiting the click reaction between appropriate Baylis-Hillman derived precursors and azidothymidine (AZT), all of which have been fully characterised using spectroscopic techniques. These conjugates, designed as potential dual-action HIV-1 inhibitors, were tested against the appropriate HIV-1 enzymes, i.e. HIV-1 reverse transcriptase and protease or HIV-1 reverse transcriptase and integrase. A number of the ligands have exhibited % inhibition levels and IC50 values comparable to drugs in clinical use, permitting their identification as lead compounds for the development of novel dual-action inhibitors. In silico docking of selected ligands into the active sites of the respective enzymes has provided useful insight into binding conformations and potential hydrogen-bonding interactions with active-site amino acid residues. A series of furocoumarin carboxamide derivatives have been synthesised in four steps starting from resorcinol and these compounds have also been tested for HIV-1 integrase inhibition activity. The structures of unexpected products isolated from Aza-Baylis-Hillman reactions of N-tosylaldimines have been elucidated by spectroscopic analysis, and confirmed by single crystal X-ray analysis. A mechanism for what appears to be an unprecedented transformation has been proposed. Microwave-assisted SeO₂ oxidation of Baylis-Hillman-derived 3-methylcoumarins has provided convenient and efficient access to coumarin-3-carbaldehydes, and a pilot study has revealed the potential of these coumarin-3-carbaldehydes as scaffolds for the construction of tricyclic compounds. The HCl-catalysed reaction of tert-butyl acrylate derived Baylis-Hillman adducts has been shown to afford 3-(chloromethyl)coumarins and α-(chloromethyl)cinnamic acids, the Zstereochemistry of the latter being established by X-ray crystallography. ¹H NMR-based experimental kinetic and DFT-level theoretical studies have been undertaken to establish the reaction sequence and other mechanistic details. Base-catalysed cyclisation on the other hand, has been shown to afford 2H-chromene rather than coumarin derivatives.

O presente trabalho teve por objetivo estudar a influência de um ativador de plantas e de dois fungicidas sobre o comportamento de plantas de tomate (Lycopersicon esculentum Mill.), cultivadas em vasos no interior de casa-de-vegetação, no município de Piedade, SP, e submetidas a diferentes condições de fornecimento de água. Os produtos químicos aplicados de forma isolada foram respectivamente dois fungicidas, a piraclostrobina (PRT) e a azoxistrobina (AZT); um ativador de plantas, o acibenzolar-s-metil (ASM). Foi incluída uma testemunha, sem aplicações de produtos. Todos os tratamentos mantiveram-se sob quatro níveis de água (90%, 72 %, 54% e 36% da capacidade de recipiente do substrato). Foram realizadas quatro aplicações dos produtos, sendo a primeira um dia antes do plantio definitivo das mudas, a segunda aos 10 dias após o plantio (DAP), seguindo-se mais duas aplicações com intervalo de 10 dias entre as mesmas. As avaliações foram efetuadas medindo os seguintes parâmetros: a) peso da massa seca da raiz, da parte aérea e total de cada planta aos 30 e 50 DAP; b) determinação do teor de clorofila das plantas aos 35 DAP, tomando-se como padrão o segundo folíolo da primeira folha abaixo do primeiro cacho floral; c) altura das plantas aos 29 e 49 DAP; d) número de folhas abaixo do primeiro cacho floral, aos 29 DAP; e) número total de folhas por planta aos 29 DAP; f) porcentagem de plantas com o primeiro cacho floral totalmente aberto aos 28 DAP; g) sintomas de deficiência hídrica aos 7 dias após a terceira e quarta aplicação dos produtos. Os resultados indicaram que as aplicações do acibenzolar-s-metil (ASM), piraclostrobina (PRT) e azoxistrobina (AZT) evitaram sintomas visíveis de murcha ocasionada pelo estresse hídrico, enquanto que em situações com maiores níveis de fornecimento de água, ocorreu maior acúmulo de matéria seca nas raízes e na parte aérea do tomateiro. / The aim of this study was to evaluate the influence of a systemic acquired resistance activator and two fungicides on tomato (Lycopersicon esculentum Mill.) plants, cultivated in pots in a greenhouse, which was exposed to different conditions of water supply. The products which were sprayed without tank mixtures (applied in their isolated form), were respectively two fungicides: piraclostrobina (PRT) and azoxistrobina (AZT); and one systemic acquired resistance activator, the acibenzolar-s-methyl (ASM), and one without products. All treatments were rent on four water levels (90%, 72%, 54% and 36% of container capacity). Four sprays of these produtcs were done: the first was done one day before planting, and the second 10 days after planting. Two more spray was done with 10 days interval between them. The following parameters were taken into measured to do the evaluations: a) dry weights of the root mass, the leaf area, and the entirely plant at 30 and 50 days after the planting (DAP); b) determination of the chlorophyll contents of the plants at 35 DAP, taking as the standard the second leaflet of the first leaf, immediately bellow the first inflorescence; c) plant height at 29 and 49 DAP; d) number of leaves below the first inflorescence at 29 DAP; e) total number of leaves for each plant at 29 DAP; f) percentage of plants with the first inflorescence totally opened at 28 DAP; g) water stress symptoms evaluation at the 7th day after the third and the fourth product sprays. The results indicated that the sprays of acibenzolar-s-methyl (ASM), piraclostrobina (PRT) and azoxistrobina (AZT) avoided the visible wilt symptoms due to the hydric stress, while in situations with higher water supply levels, the accumulation of dry material in the roots and in the leaf area of tomato plants increased.

Thesis (Dr.P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 1999. / Includes bibliographical references (leaves 127-136).

The overall approach in the present investigation has been to explore applications of the Morita-Baylis-Hillman (MBH) reaction in asymmetric synthesis and in the continuation of systems with medicinal potential. To this end, a series of varied camphor-derived acrylate esters was prepared to serve as chiral substrates in asymmetric Morita-Baylis- Hillman reactions. Reduction of N-substituted camphor-10-sulfonamides afforded the 3- exo-hydroxy derivatives as the major products. Acylation of the corresponding sodium alkoxides gave the desired 3-exo-acrylate esters, isolation of which was complicated by concomitant formation of hydrochlorinated and diastereomeric competition products. Bulky camphorsulfonamides containing alkyl, dialkyl, aromatic and adamantyl groups were selected as N-substituents with the view of achieving stereoselective outcome in subsequent MBH reactions. The synthesis of novel camphor-derived Morita-Baylis-Hillman adducts using various pyridine-carboxaldehydes proceeded with exceptionally high yields with diastereoselectivities ranging from 7-33 % d.e. Both 1D and 2D NMR and HRMS techniques were employed to confirm the structures and an extensive study of the electropositive fragmentation patterns of a number of camphor-derived chiral acrylate esters was conducted. Attention has also been given to the application of MBH methodology in the construction of heterocyclic ‘cinnamate-like’ AZT conjugates which were designed to serve as dualaction HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. A number of pyridine carboxaldehyde-derived MBH adducts were synthesized using methyl, ethyl and t-butyl acrylates in the presence of 3-hydroxyquinuclidine (3-HQ) as catalyst. The yields for these reactions were excellent. The resulting MBH adducts were acetylated and subjected to aza-Michael addition using propargylamine. The resulting alkylamino compounds were then used in ‘Click reactions’ to form the targeted AZT-conjugates in moderate to excellent yield. In silico docking of computer modelled AZT-conjugates into the HIV-1 integrase and reverse transcriptase enzyme-active sites and potential hydrogen-bonding interaction with active-site amino acid residues were identified. The electrospray MS fragmentations of the AZT and the novel AZT-conjugates were also investigated and common fragmentation pathways were identified.

O presente trabalho teve por objetivo estudar a influência de um ativador de plantas e de dois fungicidas sobre o comportamento de plantas de tomate (Lycopersicon esculentum Mill.), cultivadas em vasos no interior de casa-de-vegetação, no município de Piedade, SP, e submetidas a diferentes condições de fornecimento de água. Os produtos químicos aplicados de forma isolada foram respectivamente dois fungicidas, a piraclostrobina (PRT) e a azoxistrobina (AZT); um ativador de plantas, o acibenzolar-s-metil (ASM). Foi incluída uma testemunha, sem aplicações de produtos. Todos os tratamentos mantiveram-se sob quatro níveis de água (90%, 72 %, 54% e 36% da capacidade de recipiente do substrato). Foram realizadas quatro aplicações dos produtos, sendo a primeira um dia antes do plantio definitivo das mudas, a segunda aos 10 dias após o plantio (DAP), seguindo-se mais duas aplicações com intervalo de 10 dias entre as mesmas. As avaliações foram efetuadas medindo os seguintes parâmetros: a) peso da massa seca da raiz, da parte aérea e total de cada planta aos 30 e 50 DAP; b) determinação do teor de clorofila das plantas aos 35 DAP, tomando-se como padrão o segundo folíolo da primeira folha abaixo do primeiro cacho floral; c) altura das plantas aos 29 e 49 DAP; d) número de folhas abaixo do primeiro cacho floral, aos 29 DAP; e) número total de folhas por planta aos 29 DAP; f) porcentagem de plantas com o primeiro cacho floral totalmente aberto aos 28 DAP; g) sintomas de deficiência hídrica aos 7 dias após a terceira e quarta aplicação dos produtos. Os resultados indicaram que as aplicações do acibenzolar-s-metil (ASM), piraclostrobina (PRT) e azoxistrobina (AZT) evitaram sintomas visíveis de murcha ocasionada pelo estresse hídrico, enquanto que em situações com maiores níveis de fornecimento de água, ocorreu maior acúmulo de matéria seca nas raízes e na parte aérea do tomateiro. / The aim of this study was to evaluate the influence of a systemic acquired resistance activator and two fungicides on tomato (Lycopersicon esculentum Mill.) plants, cultivated in pots in a greenhouse, which was exposed to different conditions of water supply. The products which were sprayed without tank mixtures (applied in their isolated form), were respectively two fungicides: piraclostrobina (PRT) and azoxistrobina (AZT); and one systemic acquired resistance activator, the acibenzolar-s-methyl (ASM), and one without products. All treatments were rent on four water levels (90%, 72%, 54% and 36% of container capacity). Four sprays of these produtcs were done: the first was done one day before planting, and the second 10 days after planting. Two more spray was done with 10 days interval between them. The following parameters were taken into measured to do the evaluations: a) dry weights of the root mass, the leaf area, and the entirely plant at 30 and 50 days after the planting (DAP); b) determination of the chlorophyll contents of the plants at 35 DAP, taking as the standard the second leaflet of the first leaf, immediately bellow the first inflorescence; c) plant height at 29 and 49 DAP; d) number of leaves below the first inflorescence at 29 DAP; e) total number of leaves for each plant at 29 DAP; f) percentage of plants with the first inflorescence totally opened at 28 DAP; g) water stress symptoms evaluation at the 7th day after the third and the fourth product sprays. The results indicated that the sprays of acibenzolar-s-methyl (ASM), piraclostrobina (PRT) and azoxistrobina (AZT) avoided the visible wilt symptoms due to the hydric stress, while in situations with higher water supply levels, the accumulation of dry material in the roots and in the leaf area of tomato plants increased.

This dissertation is a challenge to the Pentecostal churches, particularly, the Apostolic Faith Mission Church in Tumahole, to take an action in meeting the challenges posed by HIV/AIDS. This disease, HIV/AIDS, is the latest enemy to human life that the nations are faced with. In the newspapers like Sowetan, there is an article almost daily about HIV and AIDS. In this dissertation, I have tried to show shocking figures of how this disease is spreading in Africa. The seriousness of the disease, unlike other diseases, is its in curability. The secular organisations are far ahead of the churches in as far as the relevant programmes on combating HIV/AIDS are concerned. Despite these massive programmes, the disease is spreading like the wild fire. Deducing from this background, it is no longer the question of whether the Pentecostal churches have any role to play, but what specific role should the church play in this challenge. In this challenging times, many people look at the church as one of the most important institute that would play a positive role in bringing hope to the hopeless. / Christian Spirituality, Church History and Missiology / M. Th. (Missiology (Urban Ministry))

This dissertation is a challenge to the Pentecostal churches, particularly, the Apostolic Faith Mission Church in Tumahole, to take an action in meeting the challenges posed by HIV/AIDS. This disease, HIV/AIDS, is the latest enemy to human life that the nations are faced with. In the newspapers like Sowetan, there is an article almost daily about HIV and AIDS. In this dissertation, I have tried to show shocking figures of how this disease is spreading in Africa. The seriousness of the disease, unlike other diseases, is its in curability. The secular organisations are far ahead of the churches in as far as the relevant programmes on combating HIV/AIDS are concerned. Despite these massive programmes, the disease is spreading like the wild fire. Deducing from this background, it is no longer the question of whether the Pentecostal churches have any role to play, but what specific role should the church play in this challenge. In this challenging times, many people look at the church as one of the most important institute that would play a positive role in bringing hope to the hopeless. / Christian Spirituality, Church History and Missiology / M. Th. (Missiology (Urban Ministry))