Thesis (Ph. D.)--University of Wisconsin, 1965. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Além do controle de fungos fitopatogênicos, muitos fungicidas produzem efeitos fisiológicos positivos na planta, contribuindo para a melhoria da produtividade da cultura mesmo na ausência de doenças. O objetivo deste trabalho foi verificar se o fungicida Fluxapiroxade, aplicado de forma isolada e e em mistura com a Piraclostrobina, exerce algum efeito fisiológico na cultura de soja. Para tal, foram conduzidos dois experimentos (I - em campo e II - em câmara de crescimento), em blocos ao acaso, comparando seis tratamentos: [1] Testemunha, [2] Ciproconazol (100 g.ha-1 i.a), [3] Piraclostrobina (100 g.ha-1 i.a.), [4] Fluxapiroxade (50 g.ha-1 i.a.), [5] Fluxapiroxade (50 g.ha-1 i.a.) + Piraclostrobina (100 g.ha-1 i.a.) e [6] Piraclostrobina (75 g.ha-1 i.a). No experimento I, os tratamentos foram aplicados em R1 e R5.1, sendo avaliadas(os): a atividade das enzimas antioxidantes (superóxido dismutase, guaiacol peroxidase e catalase) no primeiro, quarto e sétimo dia após cada aplicação; o índice de área foliar aos 20 dias após cada aplicação; a massa de matéria seca de folha, haste e órgãos reprodutivos aos 20 dias após cada aplicação; o número de vagens por planta em R6, a produtividade e a massa de 1000 grãos. No experimento II, os tratamentos foram aplicados em V7 e foram avaliadas: a fotossíntese líquida, a respiração, a condutância estomática, a transpiração e a temperatura foliar das plantas, um dia após a aplicação, por meio de um analisador infra-vermelho de gás (IRGA). Não foram observadas alterações no índice de área foliar, massa de matéria seca, respiração, transpiração, condutância estomática, temperatura foliar, número de vagens e massa de 1000 grãos para o tratamento Fluxapiroxade, tanto isolado como em mistura com a Piraclostrobina. Porém, a aplicação do Fluxapiroxade isolado reduziu a atividade das enzimas antioxidantes e também a produtividade, embora tenha elevado a taxa fotossintética líquida. Em mistura com a Piraclostrobina, houve uma redução da atividade das enzimas antioxidantes, o que refletiu em uma tendência de prejuízo à produtividade. Por outro lado, o fungicida Piraclostrobina (75 g.ha-1) apresentou maiores massa de matéria seca de flor, atividade das enzimas antioxidantes, taxa fotossintética líquida e produtividade, o que sugere uma atuação benéfica desse fungicida no metabolismo fotossintético e antioxidante da planta. Na dose de 100 g.ha-1, entretanto, a Piraclostrobina reduziu a atividade das enzimas antioxidantes e a produtividade, parecendo exercer efeito contrário àquele observado para a dose de 75 g.ha-1, embora não tenha apresentado qualquer sintoma de fitotoxicidade. / Beyond the control of plant pathogenic fungi, many fungicides produce positive physiological effects on plants, contributing to crop yield even in the absence of disease. The objective of this research is to verify if the fungicide Fluxapyroxad, alone and mixed with Pyraclostrobin, has a physiological effect on soybean. Two experiments were carried out (I - field and II - growth chamber), in a randomized block, comparing six treatments: [1] Control, [2] Ciproconazol (100 g.ha-1 a.i.), [3] Pyraclostrobin (100 g.ha-1 a.i.), [4] Fluxapyroxad (50 g.ha-1 a.i.), [5] Fluxapyroxad (50 g.ha-1 a.i.) + Pyraclostrobin (100 g.ha-1 a.i.) and [6] Pyraclostrobin (75 g.ha-1 a.i.). Experiment I was conducted with five replications and treatments were sprayed on the leaves, at stages R1 and R5.1. The activity of antioxidant enzymes (superoxide dismutase, catalase and guaiacol peroxidase) was measured on the first, fourth and seventh day after each application. The leaf area index and the leaf, stem and flower/pod dry matter were measured 20 days after each application. The number of pods per plant, yield and weight of 1000 seeds were also measured. Experiment II was conducted with four replications and treatments were sprayed only at V7, due to limitation of space in the growth chamber. Net photosynthesis, respiration, stomatal conductance, transpiration and leaf temperature were measured one day after the application, by a \"Infra-Red Gas analyser\" (IRGA). No changes in leaf area index, dry matter, respiration, transpiration, stomatal conductance, leaf temperature, number of pods or weight of 1000 seeds were observed for the treatment Fluxapyroxad, neither alone nor in combination with Pyraclostrobin. The application of Fluxapyroxad alone reduced both the activity of antioxidant enzymes and yield, although net photosynthesis was increased. Fluxapyroxad + Pyraclostrobin reduced the activity of antioxidant enzymes and showed a tendency to reduce yield. Moreover, the treatment with Pyraclostrobin (75 g.ha-1) was superior in terms of flower dry matter, antioxidant enzyme activity, net photosynthetic rate and yield, suggesting that this fungicide may have a positive effect on photosynthetic and antioxidative metabolism of the soybean plant. Pyraclostrobin (100 g.ha-1), however, reduced antioxidant enzyme activity and yield, which suggests that an elevation in the Pyraclostrobin dose promotes the opposite effect of that observed for the recommended dose, although no phytotoxicity symptoms have appeared.

Além do controle de fungos fitopatogênicos, muitos fungicidas produzem efeitos fisiológicos positivos na planta, contribuindo para a melhoria da produtividade da cultura mesmo na ausência de doenças. O objetivo deste trabalho foi verificar se o fungicida Fluxapiroxade, aplicado de forma isolada e e em mistura com a Piraclostrobina, exerce algum efeito fisiológico na cultura de soja. Para tal, foram conduzidos dois experimentos (I - em campo e II - em câmara de crescimento), em blocos ao acaso, comparando seis tratamentos: [1] Testemunha, [2] Ciproconazol (100 g.ha-1 i.a), [3] Piraclostrobina (100 g.ha-1 i.a.), [4] Fluxapiroxade (50 g.ha-1 i.a.), [5] Fluxapiroxade (50 g.ha-1 i.a.) + Piraclostrobina (100 g.ha-1 i.a.) e [6] Piraclostrobina (75 g.ha-1 i.a). No experimento I, os tratamentos foram aplicados em R1 e R5.1, sendo avaliadas(os): a atividade das enzimas antioxidantes (superóxido dismutase, guaiacol peroxidase e catalase) no primeiro, quarto e sétimo dia após cada aplicação; o índice de área foliar aos 20 dias após cada aplicação; a massa de matéria seca de folha, haste e órgãos reprodutivos aos 20 dias após cada aplicação; o número de vagens por planta em R6, a produtividade e a massa de 1000 grãos. No experimento II, os tratamentos foram aplicados em V7 e foram avaliadas: a fotossíntese líquida, a respiração, a condutância estomática, a transpiração e a temperatura foliar das plantas, um dia após a aplicação, por meio de um analisador infra-vermelho de gás (IRGA). Não foram observadas alterações no índice de área foliar, massa de matéria seca, respiração, transpiração, condutância estomática, temperatura foliar, número de vagens e massa de 1000 grãos para o tratamento Fluxapiroxade, tanto isolado como em mistura com a Piraclostrobina. Porém, a aplicação do Fluxapiroxade isolado reduziu a atividade das enzimas antioxidantes e também a produtividade, embora tenha elevado a taxa fotossintética líquida. Em mistura com a Piraclostrobina, houve uma redução da atividade das enzimas antioxidantes, o que refletiu em uma tendência de prejuízo à produtividade. Por outro lado, o fungicida Piraclostrobina (75 g.ha-1) apresentou maiores massa de matéria seca de flor, atividade das enzimas antioxidantes, taxa fotossintética líquida e produtividade, o que sugere uma atuação benéfica desse fungicida no metabolismo fotossintético e antioxidante da planta. Na dose de 100 g.ha-1, entretanto, a Piraclostrobina reduziu a atividade das enzimas antioxidantes e a produtividade, parecendo exercer efeito contrário àquele observado para a dose de 75 g.ha-1, embora não tenha apresentado qualquer sintoma de fitotoxicidade. / Beyond the control of plant pathogenic fungi, many fungicides produce positive physiological effects on plants, contributing to crop yield even in the absence of disease. The objective of this research is to verify if the fungicide Fluxapyroxad, alone and mixed with Pyraclostrobin, has a physiological effect on soybean. Two experiments were carried out (I - field and II - growth chamber), in a randomized block, comparing six treatments: [1] Control, [2] Ciproconazol (100 g.ha-1 a.i.), [3] Pyraclostrobin (100 g.ha-1 a.i.), [4] Fluxapyroxad (50 g.ha-1 a.i.), [5] Fluxapyroxad (50 g.ha-1 a.i.) + Pyraclostrobin (100 g.ha-1 a.i.) and [6] Pyraclostrobin (75 g.ha-1 a.i.). Experiment I was conducted with five replications and treatments were sprayed on the leaves, at stages R1 and R5.1. The activity of antioxidant enzymes (superoxide dismutase, catalase and guaiacol peroxidase) was measured on the first, fourth and seventh day after each application. The leaf area index and the leaf, stem and flower/pod dry matter were measured 20 days after each application. The number of pods per plant, yield and weight of 1000 seeds were also measured. Experiment II was conducted with four replications and treatments were sprayed only at V7, due to limitation of space in the growth chamber. Net photosynthesis, respiration, stomatal conductance, transpiration and leaf temperature were measured one day after the application, by a \"Infra-Red Gas analyser\" (IRGA). No changes in leaf area index, dry matter, respiration, transpiration, stomatal conductance, leaf temperature, number of pods or weight of 1000 seeds were observed for the treatment Fluxapyroxad, neither alone nor in combination with Pyraclostrobin. The application of Fluxapyroxad alone reduced both the activity of antioxidant enzymes and yield, although net photosynthesis was increased. Fluxapyroxad + Pyraclostrobin reduced the activity of antioxidant enzymes and showed a tendency to reduce yield. Moreover, the treatment with Pyraclostrobin (75 g.ha-1) was superior in terms of flower dry matter, antioxidant enzyme activity, net photosynthetic rate and yield, suggesting that this fungicide may have a positive effect on photosynthetic and antioxidative metabolism of the soybean plant. Pyraclostrobin (100 g.ha-1), however, reduced antioxidant enzyme activity and yield, which suggests that an elevation in the Pyraclostrobin dose promotes the opposite effect of that observed for the recommended dose, although no phytotoxicity symptoms have appeared.

A situação da tuberculose (TB) foi alterada de forma significativa pela síndrome de imunodeficiência adquirida (SIDA ou AIDS) e pelo aparecimento de novas cepas do Mycobacterium tuberculosis resistentes ao tratamento quimioterápico, que justificariam a pesquisa de novos agentes antimicobacterianos. Alvos interessantes têm emergido para o planejamento racional de novos fármacos contra a TB, particularmente, considerando processos metabólicos específicos que ocorrem durante a biossíntese da parede celular micobacteriana e que envolvem a síntese de ácidos graxos (FAS-II, fatty acid synthase). O sistema FAS-II constitui diferença bioquímica importante entre mamíferos e micobatérias. A enzima enoil-acp (acyl carrier protein, proteína acil-carregadora) redutase (ENR) é alvo determinante no sistema FAS-II, responsável pela etapa de alongamento dos ácidos micólicos, que são os principais componentes da parede celular do M. tuberculosis. O presente projeto tem como objetivo a aplicação de metodologias do planejamento de fármacos auxiliado por computador, CADD (Computer-Aided Drug Design), em um conjunto de derivados pirrolidina carboxamidas descritos como inibidores potenciais da ENR do M. tuberculosis (InhA) com intuito de mapear o farmacóforo, investigar a orientação dos ligantes no sítio ativo e os tipos de interações que se estabelecem com os resíduos de aminoácidos do sítio de interação. Inicialmente, investigaram-se as relações quantitativas entre estrutura química e atividade biológica (QSAR, quantitative structure-activity relationships) com aplicação de abordagem multivariada. O melhor modelo QSAR indicou que propriedades estruturais, termodinâmicas e eletrônicas devem ser consideradas no processo de planejamento e proposição de novos protótipos potencialmente tuberculostáticos. / The incidence of tuberculosis (TB) disease has significantly changed considering the acquired immunodeficiency syndrome (AIDS) co-infection as well as the emergence of new Mycobacterium tuberculosis strains resistant to the currently chemotherapy. These facts support the search for novel antimycobacterial agents. Interesting targets have been elucidated and could be used for the rational design of new drugs against TB, primarily those related to specific biochemical metabolic pathways that occur during the cell wall biosynthesis, specially involved in the fatty acid synthase (FAS) system. The FAS-II system is an important biochemical difference between mammals and mycobacteria. The enoyl-ACP reductase (ENR) is the key enzyme in the FAS-II system, responsible for the elongation step of mycolic acids, which are the major components in the M. tuberculosis cell wall. This research project aims the application of computer-aided drug design (CADD) methodologies to a set of pyrrolidine carboxamide derivatives, which were previously reported as potential M. tuberculosis ENR (InhA) inhibitors, for mapping the pharmacophore, investigating the ligands\' orientation at the active site and also the interaction types regarding the amino acid residues in the active site. Initially, the quantitative structure-activity relationships (QSAR) were performed applying a multivariate approach. The best QSAR model indicated the structural, thermodynamic, and electronic properties must be taken into account in the design of novel leads as potential antituberculosis agents.

A utilização de modelos matemáticos na agricultura é de fundamental importância para o desenvolvimento do setor agrícola. O fungo Phakopsora pachyrhizi configura-se como um importante patógeno que parasita a cultura da soja, causando prejuízos bilionários ao agronegócio brasileiro. Na última década, observou-se a rápida perda de eficácia dos principais fungicidas utilizados para seu controle, caracterizando um processo de resistência para os fungicidas DMIs e Q0I. Recentemente, novas moléculas foram introduzidas no mercado para a cultura da soja - fungicidas inibidores da Succinato Desidrogenase (SDHI) - com o objetivo de aumentar os níveis de controle sobre o patógeno. Nesse contexto, o trabalho teve como objetivo a elaboração de um modelo determinístico com análise de incerteza que possibilitasse a previsão do tempo de resistência (longevidade) do patógeno para os novos fungicidas, contribuindo, dessa forma, para a elaboração de novas estratégias de manejo a fim de proporcionar maior vida útil a tais moléculas. / The use of mathematical models in agriculture have fundamental importance for the development of the agricultural sector. The fungus Phakopsora pachyrhizi is an important pathogen which parasitizes the soybean crop, causing billions of losses to Brazilian agribusiness. In the last decade, it was observed the rapid loss of effectiveness of the main fungicides used for its control, characterizing a resistance process for the fungicides DMIs and Q0I. Recently, new molecules were introduced to the soybean crop - Succinate Dehydrogenase (SDHI) inhibitor fungicides whose the objective is increase the efficiency over the pathogen. In this context, the objective of this work was the elaboration of a deterministic model with uncertainty analysis that would allow the prediction of the resistance time (longevity) of the pathogen to the new fungicides, thus contributing to the elaboration of new management strategies to provide longer life to such molecules.

A situação da tuberculose (TB) foi alterada de forma significativa pela síndrome de imunodeficiência adquirida (SIDA ou AIDS) e pelo aparecimento de novas cepas do Mycobacterium tuberculosis resistentes ao tratamento quimioterápico, que justificariam a pesquisa de novos agentes antimicobacterianos. Alvos interessantes têm emergido para o planejamento racional de novos fármacos contra a TB, particularmente, considerando processos metabólicos específicos que ocorrem durante a biossíntese da parede celular micobacteriana e que envolvem a síntese de ácidos graxos (FAS-II, fatty acid synthase). O sistema FAS-II constitui diferença bioquímica importante entre mamíferos e micobatérias. A enzima enoil-acp (acyl carrier protein, proteína acil-carregadora) redutase (ENR) é alvo determinante no sistema FAS-II, responsável pela etapa de alongamento dos ácidos micólicos, que são os principais componentes da parede celular do M. tuberculosis. O presente projeto tem como objetivo a aplicação de metodologias do planejamento de fármacos auxiliado por computador, CADD (Computer-Aided Drug Design), em um conjunto de derivados pirrolidina carboxamidas descritos como inibidores potenciais da ENR do M. tuberculosis (InhA) com intuito de mapear o farmacóforo, investigar a orientação dos ligantes no sítio ativo e os tipos de interações que se estabelecem com os resíduos de aminoácidos do sítio de interação. Inicialmente, investigaram-se as relações quantitativas entre estrutura química e atividade biológica (QSAR, quantitative structure-activity relationships) com aplicação de abordagem multivariada. O melhor modelo QSAR indicou que propriedades estruturais, termodinâmicas e eletrônicas devem ser consideradas no processo de planejamento e proposição de novos protótipos potencialmente tuberculostáticos. / The incidence of tuberculosis (TB) disease has significantly changed considering the acquired immunodeficiency syndrome (AIDS) co-infection as well as the emergence of new Mycobacterium tuberculosis strains resistant to the currently chemotherapy. These facts support the search for novel antimycobacterial agents. Interesting targets have been elucidated and could be used for the rational design of new drugs against TB, primarily those related to specific biochemical metabolic pathways that occur during the cell wall biosynthesis, specially involved in the fatty acid synthase (FAS) system. The FAS-II system is an important biochemical difference between mammals and mycobacteria. The enoyl-ACP reductase (ENR) is the key enzyme in the FAS-II system, responsible for the elongation step of mycolic acids, which are the major components in the M. tuberculosis cell wall. This research project aims the application of computer-aided drug design (CADD) methodologies to a set of pyrrolidine carboxamide derivatives, which were previously reported as potential M. tuberculosis ENR (InhA) inhibitors, for mapping the pharmacophore, investigating the ligands\' orientation at the active site and also the interaction types regarding the amino acid residues in the active site. Initially, the quantitative structure-activity relationships (QSAR) were performed applying a multivariate approach. The best QSAR model indicated the structural, thermodynamic, and electronic properties must be taken into account in the design of novel leads as potential antituberculosis agents.

A utilização de modelos matemáticos na agricultura é de fundamental importância para o desenvolvimento do setor agrícola. O fungo Phakopsora pachyrhizi configura-se como um importante patógeno que parasita a cultura da soja, causando prejuízos bilionários ao agronegócio brasileiro. Na última década, observou-se a rápida perda de eficácia dos principais fungicidas utilizados para seu controle, caracterizando um processo de resistência para os fungicidas DMIs e Q0I. Recentemente, novas moléculas foram introduzidas no mercado para a cultura da soja - fungicidas inibidores da Succinato Desidrogenase (SDHI) - com o objetivo de aumentar os níveis de controle sobre o patógeno. Nesse contexto, o trabalho teve como objetivo a elaboração de um modelo determinístico com análise de incerteza que possibilitasse a previsão do tempo de resistência (longevidade) do patógeno para os novos fungicidas, contribuindo, dessa forma, para a elaboração de novas estratégias de manejo a fim de proporcionar maior vida útil a tais moléculas. / The use of mathematical models in agriculture have fundamental importance for the development of the agricultural sector. The fungus Phakopsora pachyrhizi is an important pathogen which parasitizes the soybean crop, causing billions of losses to Brazilian agribusiness. In the last decade, it was observed the rapid loss of effectiveness of the main fungicides used for its control, characterizing a resistance process for the fungicides DMIs and Q0I. Recently, new molecules were introduced to the soybean crop - Succinate Dehydrogenase (SDHI) inhibitor fungicides whose the objective is increase the efficiency over the pathogen. In this context, the objective of this work was the elaboration of a deterministic model with uncertainty analysis that would allow the prediction of the resistance time (longevity) of the pathogen to the new fungicides, thus contributing to the elaboration of new management strategies to provide longer life to such molecules.

Malaria is one of the deadliest diseases known to mankind. In 2010, 219 million cases were reported, and 666,000 deaths were attributed to this disease. In the past, pyrethroid-treated mosquito nets have shown efficacy in reducing malaria transmission in many malaria endemic regions. However, an upsurge in the mosquito population that is resistant to pyrethroids threatens to compromise the efficacy of pyrethroid-treated bed nets. In an effort to develop another class of insecticide with a different mode of action, we have explored three classes of five membered heterocyclic carbamates (isoxazol-3-yl, pyrazol-5-yl, and pyrazol-4-yl), and 3-oxoisoxazole- 2(3H)-carboxamide as acetylcholinesterase inhibitors (AChE) targeting wild type (G3) and resistant (Akron) malaria mosquito Anopheles gambiae (Ag). Isoxazole carboxamide and carbamates were obtained regioselectively through judicious use of two different protocols. The final products were characterized and identified using ¹H and ¹³C NMR, and mass spectroscopy. In addition, the carboxamide structure was confirmed using X-ray diffraction. Several of the novel carbamates and carboxamides evaluated exhibited excellent toxicity towards susceptible G3 and resistant Akron strain An. gambiae (48f LC₅₀ G3 = 41 μg/mL, LC₅₀ Akron = 58 μg/mL, and 47i LC₅₀ G3 = 38 μg/mL, LC₅₀ Akron = 40 μg/mL). Hence, achieving the resistance- breaking goal. On the contrary, the commercial aryl methylcarbamates currently approved for indoor residual sprays (IRS) showed no potency towards the resistant strain An. gambiae (LC₅₀ G3 = 16-42 μg/mL, and LC₅₀ Akron >5,000 μg/mL). Further, we observed low toxicological cross-resistance ratios (RR) for the toxic isoxazol-3-yl and pyrazol-4-yl carbamates, and 3- oxoisoxazole-2(3H)-carboxamides (RR = 0.5-2.0). Amongst the commercial AChE inhibitors approved for IRS, only aldicarb exhibited such low RR (RR = 0.5), whereas the RR for commercial aryl methylcarbamates exceed 130-fold. The low RR observed for these novel heterocyclic inhibitors would certainly be favorable for a new anticholinesterase-based mosquitocide targeting both the susceptible and resistant strain mosquitoes. Although the overall selectivity (Ag vs human) did not exceed 24-fold, the heterocyclic carbamates and carboxamides synthesized by the author showed appreciable inhibition of resistant AChE (G119S) in comparison to commercial aryl carbamates, which showed no inhibition at all. During the course of this project, the isoxazol-3-yl and pyrazol-5-yl methylcarbamates proved to be unstable, and thus could not be isolated. The synthesis of pyrazol-4-yl methylcarbamates using N-methylcarbamoyl chloride proved particularly challenging due to the formation of by-products called allophanates. The similar Rf of the by-product and the desired final product made the isolation laborious and time-consuming. We have successfully overcome this problem by employing a new protocol, where triphosgene served as the carbonylating agent and N-methylamine in THF was used as the amine source. In addition, we have also developed another one-pot protocol for a safer synthesis of pyrazol-4-yl methylcarbamates utilizing 1,1- carbonyldiimidazole (CDI), and N-methylamine hydrogen chloride salt. With the pyrazol-4-yl core, apart from achieving excellent toxicity towards both strains of An. gambiae, we have also achieved excellent AgAChE vs hAChE selectivity (Ag vs h >100-fold). Due to our continued interest in developing this core, we have devised a convenient, scalable, no-column approach for the synthesis an intermediate 103 that can be utilized to synthesize these compounds more efficiently. / Ph. D.

Worldwide, malaria is one of the deadliest diseases. In 2016 it sickened 216 million people and caused 445,000 deaths. In order to control the spread of this deadly diseases to human, we can either target the mosquito vector (Anopheles gambiae) or the parasite (Plasmodium falciparum). Due to recent emergence of resistance to current insecticides and antimalarial drugs there is a pressing need to discover and develop new agents that engage new targets in these organisms. To circumvent the effect of resistance to pyrethroid insecticides on the efficacy of insecticide treated nets (ITNs), the use of acetylcholinesterase (AChE) inhibitors on ITNs has drawn attention. In the first project, we explored a small library of γ- substituted oxoisoxazole- 2(3H)-carboxamides and isoxazol-3-yl carbamates, and nitriles as AChE inhibitors targeting wild- type (G3) and resistant (Akron) An. gambiae mosquito. In total 23 compounds were synthesized and evaluated. Both carbamates and carboximides with a 2-cyclopropylethyl side chain (1-87a and 1-88a) were extremely toxic to Akron mosquitos, yet these compounds did not exhibit appreciable selectivity between human and An. gambiae AChE. Unfortunately, none of the nitriles showed appreciable toxicity to G3 strain of the mosquitoes, nor did they inhibit An. gambiae AChE. In the second project, conducted in collaboration with Professor Michael Klemba, we focused on the mode of action of an established antimalarial drug, Mefloquine (MQ). Dr. Klemba's recently developed amino acid efflux assay was used to determine the effect of MQ and its open-ring analogs on hemoglobin endocytosis and catabolism in P. falciparum-infected erythrocytes. In total 26 MQ analogs were synthesized and 18 were studied in depth to determine their potency to inhibit leucine (Leu) efflux and parasite growth (SYBR Green). An excellent correlation (R² = 0.98) over nearly 4 log units was seen for these 18 compounds in the two assays. These data are consistent with the hypothesis that the antimalarial action of these compounds principally derives from inhibition of hemoglobin endocytosis. After this observation, a number of photo-affinity probes were designed and synthesized in hopes of isolating the molecular target of MQ. These analogs are currently being used by Dr. Klemba in pull-down experiments. In the third project, conducted in collaboration with Professor Belen Cassera, we sought to optimize a new antimalarial drug lead that would circumvent current resistance mechanisms. In Plasmodium parasites, the methylerythritol phosphate (MEP) pathway is known to be essential for its growth. This pathway is absent in humans, presenting the opportunity to develop potentially safe and effective therapeutic candidates. Previous work in the Cassera and Carlier lab had established that MMV008138 was the only compound in the Malaria Box that targeted the MEP pathway and that it was (1R,3S)-configured. My research expanded previous efforts in the Carlier group and produced synthesis of 73 analogs of MMV008138 (3-21a'1) that were tested for growth inhibition. These analogs featured variation at the A-, B-, C- and D-ring. In the process, a novel Pictet-Spengler ring expansion reaction of ortho-substituted acetphenones was discovered. The ring-expanded products were identified by means of 1D and 2D NMR experiments, HRMS, and X-ray crystallography. Among the 73 analogs prepared, four compounds showed similar growth inhibition potency to the lead 3-21a'1. In particular, the methoxyamide 3-80a, and the fluorinated A-ring analogs 3-124a, 3-124c and 3-124d all showed excellent (500-700 nM) growth IC₅₀ values against P. falciparum. All four showed full rescue upon co-application of IPP (200 μM), confirming that they target the MEP pathway. ADME-Tox evaluation of these new analogs will soon be underway. / PHD

<p>Diss. (sammanfattning) Umeå : Umeå universitet, 1990, härtill 5 uppsatser.</p> / digitalisering@umu.se