Title from title screen. Interactive three dimensional molecular data and multiple colour images. Text presented in Hypertext Markup Language (.htm); images in standard formats (.jpg, .gif); molecules presented mostly as Cambridge Protein Data Bank format (.pdb); some molecules presented in alternative X.Mol cartesian co-ordinates format (.xyz); search facility in PERL script. Includes bibliographical references. Text, numeric and representational data System requirements: for text, any standard web browser on any platform, Netscape 2.x or higher, Internet Explorer 3.x or higher; for molecular structures, viewer such as Rasmol or preferably MDL's Chemscape Chime; for search facility , an appropriately configured web server. Links to all required software for browsing on various platforms are included in the software directory in the thesis. Mode of access: World Wide Web.

O aumento do conhecimento sobre os mecanismos macromoleculares de diversas doenças tem permitido a identificação de vários alvos terapêuticos, porém o desenvolvimento de fármacos para esses alvos não seguiu na mesma velocidade. Além disso, a presença de padrões estruturais inovadores nesses fármacos é baixa. Neste cenário, buscamos, ao mapear o espaço químico medicinal de compostos heteroaromáticos, introduzir novos fragmentos úteis no desenvolvimento de compostos bioativos inovadores. Para tanto, duas abordagens foram avaliadas: 1) Estudo da viabilidade de síntese de dois núcleos heteroaromáticos sem síntese descrita na literatura. 2) Estudo de uma nova rota sintética para obtenção do núcleo furo[2,3-b]piridina, bem como a viabilidade de sua funcionalização e aplicação no desenvolvimento de compostos com atividade antituberculose. Em relação a primeira abordagem (Capítulo 1), para o núcleo 22 (piridazina-piridona) foi possível explorar uma rota sintética que, embora, ainda não tenha sido possível obter o composto desejado, o mesmo necessita apenas de uma etapa de aromatização para ser obtido. Já para o núcleo 20 (pirido-piridazinona), após o estudo de diversas estratégias sintéticas, foi possível obtê-lo, em baixos rendimentos, e, portanto, a otimização da rota sintética, bem como a completa caracterização dele, ainda serão necessários. Durante a exploração das diversas estratégias para a síntese do núcleo 20, foi possível, a partir de resultado inesperado em uma delas, verificar uma nova rota sintética para compostos furo[2-3-b]piridina substituídos nas posições C-2 e C-3, o que foi objeto de estudo da segunda abordagem descrita nesta tese (Capítulo 2). Utilizando condições brandas e livre de metais, foi possível obter diversas furanopiridinas com diferentes substituições em C-2 (arílico ou alquílico), utilizando diversos cloretos de ácidos ou anidridos. Além disso, foi verificado que o anel furânico do núcleo furanopiridínico é estável na reação de hidrólise do éster em C-3, porém quando na presença de hidrazina é formado um novo padrão estrutural com anel pirazolona, proveniente da abertura do anel furano. Em relação a reatividade química da porção piridínica desse núcleo, em reações de ativação da ligação C-H, foi possível realizar a borilação seguida de acoplamento cruzado de Suzuki na posição C-5. Já arilação radicalar ocorreu em C-4 e a fluorinação direta em C-6. Porém, os rendimentos destas reações não foram satisfatórios. Com isso, foi avaliado a reatividade do derivado N-óxido da furanopiridina com diferentes agentes ativantes e nucleófilos. Com o uso de anidrido tríflico como agente ativante, foi possível a iodação em C-5, bromação em C-4 e hidroxilação em C-4 e C-6. Já utilizando PyBroP, como ativante, foi possível realizar reações de aminação nas posições C-4, C-5 e C-6. Esses compostos tiveram a atividade biológica contra Mycobacterium tuberculosis avaliada, onde um dos compostos apresentou atividade promissora, tanto contra cepas laboratoriais, quanto cepas de isolados clínicos multirresistentes. Além disso, esse composto apresentou alto índice de seletividade, e por ser um fragmento, permitirá futuras otimização estruturais. / The increasing knowledge about the macromolecular mechanisms of different diseases allowed the identification of several therapeutic targets over the years. However, the development of drugs to these targets did not follow the same rate. In addition, the introduction of innovative frameworks in new drugs is unsatisfactory. In this scenario, we aim to introduce new useful fragments for application in the development of innovative bioactive compounds, by charting the medicinal chemical space of heteroaromatic compounds. For this purpose, two approaches were evaluated: 1) Develop a feasible synthetic strategy to obtain two new heteroaromatic cores (Cores 20 and 22); 2) Develop a new synthetic route to obtain the furo[2,3-b]pyridine core, chemical elaborate it and screening it against Mycobacterium tuberculosis. For the first approach (Chapter 1), one aromatization step is needed to obtain core 22 (pyridazine-pyridone). On the other hand, after evaluating several synthetic strategies, it was possible to obtain core 20 (pyrido-pyridazinone) in low yields. Therefore, a synthetic route optimization and a complete characterization are still required for 20. An unexpected result in attempt to obtain core 20, resulted in a new synthetic route to furo[2-3-b]pyridine, C-2 and C- 3 substituted, that was explored in the second approach (Chapter 2). Using mild and metal-free conditions, it was possible to obtain various furopyridines with different substitutions patterns at C-2 (aryl or alkyl) using either acyl chlorides or anhydrides. In addition, the furan moiety in this core, showed to be stable under the C-3-ester hydrolysis, however, in solution, hydrazine opens the furan ring to form a new pyrazolone ring. Regarding the chemical reactivity of the pyridine moiety in the furopyridine core, it was possible to perform the C-H borylation followed by Suzuki coupling reaction at the C-5 position. Furthermore, radical arylation at C-4 and direct fluorination at C-6 had not satisfactory yields. Therefore, the reactivity of the furopyridine N-oxide derivative with nucleophiles using different activating agents was studied. Using triflic anhydride, as an activating agent, it was possible to iodinate at C-5, brominated at C-4 and hydroxylated at C-4 and C-6. Using PyBroP, as an activator, it was possible to perform amination reactions at positions C-4, C-5 and C-6. In the end, our in-house library of furopyridines was screened against Mycobacterium tuberculosis and it was found a promising selective bioactive compound against different multidrug-resistant strains of this mycobacteria. Furthermore, this compound is a fragment, which will allow future structural optimization.

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands.

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands.