Thesis (M.S.)--University of Wisconsin--Madison, 1969. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1959. / Typescript. Abstracted in Dissertation abstracts, v. 20 (1959) no. 3, p. 875-876. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-79).

Infectious diseases continue to be a major concern worldwide. They are the second leading cause of death after heart disease. Factors such as an increasing global population, travel, urbanization, global climate change and evolution of pathogens have made infectious diseases more common. Infectious diseases, particularly neglected tropical diseases (NTDs) result in many deaths worldwide. Malaria and leishmaniasis are two common (NTDs) which affect low income countries around the globe. Low cost drugs with novel mechanism of action are required to tackle the growing resistances of parasites against current drugs used in the developing world, where most of the cases occur. The first part of this manuscript (chapters 1 - 3) describes the synthesis of novel analogs active against Leishmania donovani parasite which causes leishmaniasis. Leishmaniasis is a vector-borne complex group of diseases transmitted through the bite of an infected female sand-fly. Its clinical manifestations range from the less severe (cutaneous) to fatal (visceral) forms depending upon infecting species, immunity of host and the environment. Reports have suggested the role of Heat shock protein 90 (Hsp 90) in the differentiation of the Leishmania parasite from the promastigote stage to the pathogenic amastigote stage inside the host. A series of tetrahydro-indazole, tetrahydro-pyrazolo pyridine and radicicol hybrid compounds were prepared based on known Hsp 90 inhibitors, SNX2112 and NVP-AUY922. The synthetic approach allowed us to generate a diverse library of analogs which were used to probe the hydrophobic pocket of Hsp 90 active site. The most active compound, was found to be twice more active as the clinically used drug, Miltefosine, in an infected macrophage assay with an IC50 = 0.88 µM. The second part of this manuscript (chapters 4 - 5) describes the synthesis of xanthurenic acid analogs as antimalarial drugs. Xanthurenic acid (XA) is a vital component for the gametogenesis of the Plasmodium inside the mosquito’s gut. Gametogenesis plays an important part in the continuation of the parasite’s life cycle. A series of xanthurenic acid analogs were synthesized with the aim of inducing premature exflagellation of the microgametes, thus blocking the key step required for the transmission of parasites from humans to the mosquito. A biotinylated xanthurenic acid analog and a clickable xanthurenic acid analog were also synthesized which will help us investigate the mechanism of action of xanthurenic acid in inducing gametogenesis in mosquito. In the preliminary screening efforts in an exflagellation assay, analog 4.40 showed promising activity and was more active in inducing exflagellation than xanthurenic acid. An exflagellation assay of other analogs is currently being pursued. Further investigations into the molecular target and mechanism of action are underway with the biotinylated xanthurenic acid analog.

The present work describes, for the first time, the preparation and use of a simple and efficient glassy carbon electrode (GCE) modified with multi-wall carbon nanotubes (MWCNT) and an activated-xanturenic acid (poly-XA) towards electrocatalytic NADH oxidation. For this purpose, initially, xanthurenic acid was activated in situ, generating a stable redox-active specie on the electrodic surface, which presented electrocatalytic activity towards the oxidation of NADH. The techniques used for the accomplishment of this work were the cyclic voltametry and cronoamperometry, which were used to study the behavior of the modified electrodes, for the experimental parameters optimization, for the attainment of the kinetic parameters and analytical characterization of the sensors. Hydrodynamic and cronoamperometric studies were carried out with the aim to get information on the oxidation process of NADH on the modified electrode. Through the Koutech-Levich and Cotrell plots it was possible to obtain the values for the diffusion coefficient (D) and the kinetic constant of the catalytic reaction (k) for the analyte in study. The values of the diffusion coefficient and k, determined for NADH were 2,4x10-6 cm2 s-1 and 7,82 x104 L mol-1 s-1, respectively / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Neste trabalho é descrito pela primeira vez a utilização de ácido xanturênico (AX) como mediador redox através de um simples e eficiente eletrodo de carbono vítreo (ECV) modificado com nanotubos de carbono de paredes múltiplas e ativado com AX para eletro-oxidação de NADH. Para este propósito, inicialmente, ácido xanturênico foi ativado in situ, gerando uma espécie eletroativa estável na superfície eletródica (poli-AX), o qual apresentou atividade electrocatalítica frente à oxidação de NADH. As técnicas empregadas para a realização deste trabalho foram a voltametria cíclica e cronoamperometria, as quais foram utilizadas para estudar o comportamento dos eletrodos modificados, para a otimização dos parâmetros experimentais e obtenção dos parâmetros cinéticos. Além disso, os estudos hidrodinâmicos e cronoamperométricos foram realizados com o objetivo de obter maiores informações sobre o processo de oxidação entre o NADH e o eletrodo modificado. Assim, através dos gráficos e equações de Koutech-Levich e Cottrell foi possível obter os valores para o coeficiente de difusão (D) e constante de velocidade da reação (k) para NADH. Os valores do D e de k, determinados para NADH, foram de 2,4 x10-6 cm2 s-1 e 7,84 x 105 L mol-1 s-1, respectivamente