New quinoxaline 1,4-di-n-oxide derivatives against neglected diseases
- Autores: Esther Vicente Cemborain
- Directores de la Tesis: Ignacio Aldana Moraza (dir. tes.), Silvia Perez Silanes (codir. tes.)
- Lectura: En la Universidad de Navarra ( España ) en 2007
- Idioma: español
- Tribunal Calificador de la Tesis: Antonio Monge Vega (presid.), Andres Jaso Amadoz (secret.), M. Belén Zarranz Michaus (voc.), Antonio Ramon Martínez Fernandez (voc.), Livia Vivas O'sea (voc.)
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- Resumen
NEW QUINOXALINE 1,4-DI-N-OXIDE DERIVATIVES AGAINST NEGLECTED DISEASES #RESUMEN: The neglected diseases are medically diverse infectious diseases which principally affect poor people in developing countries. This is a true challenge for Public Health because these diseases cause up to 35,000 deaths daily, there are no available vaccines to control the diseases, the drugs available for treatment are not adequate due to their toxicity, long duration, mode of administration, or the development of resistances. Tuberculosis and malaria stand out among the many neglected diseases because they are the ones that claim more human lives throughout the world than any of the other existing contagious diseases. This work attempts to take advancing steps in the development of the treatment for malaria and tuberculosis by obtaining new lead-compounds that improve the activity and selectivity of the existing drugs. in order to achieve this aim, an extense bibliographic revision was first carried out, permitting the design of chemical structures with which- to initiate the project. The quinoxaline 1,4-di-N-oxide derivatives were selected due to their well-known antibacterial properties and due to the fact that said structure is bioisoster of the rings on which certain el i ni cali y used antimalarial and antituberculosis drugs are based. Both the synthesis and characterization of the molecules designed were carried out in the Drug r&d unit of the University of Navarra. The method of synthesis of these derivatives is based on the Beirut reacción, which was adapted to each series of compounds by modifying the dissolvent, catalyst or other conditions. in order to characterize each one of the synthesized compounds, the following were used: Nuclear Magnetic Resonance, infrared spectroscopy, chn Elemental Analysis, Thin Layer Chromatography and Mass Spectrometry. The synthesized derivatives were evaluated as antimalarial agents at the London School of Hygiene and Tropical Medicine. Plasmodium falciparum chloroquine-resistant and chloroquine-sensitive strains were cultured and used in the biological assay based on the incorporation of tritiated hypoxanthine by the parasite. in addition, epidermal carcinoma human cells (KB strain) were cultured for use in a cytotoxicity assay which permitted determination of the selectivity of these derivatives. The prepared molecules were also sent to the Tuberculosis Antimicrobial Acquisition and Coordinating Facility for a study on their antituberculosis activity. The results obtained aided in the search for structure-Activity Relationships (sar). in an attempt to quantify these relationships, theoretical computational Chemistry studies were carried out, developed at the Institute of Theoretical and Applied Physicochemical Research (inifta) in La Plata, Argentina. These studies principally consisted in: exploration of the conformational space of the molecules by means of molecular dynamics and the search for semi-empirical models which permit prediction of properties based on the qspr-qsar theory
