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Estudio de la actividad tripanocida y de los mecanismos de acción antiparasitaria de dos nuevas familias de nitrocompuestosAravena Castro, María de los Ángeles January 2016 (has links)
Tesis para optar al grado académico de Doctor en Química / La presente tesis doctoral exhibe un estudio químico y biológico de dos familias de
nitrocompuestos: derivados de Nitrofurano y derivados de Nitroindazol, con el propósito
principal de obtener nuevos aspectos acerca de los mecanismos de acción tripanocida de
estos potenciales nuevos fármacos, capaces de superar las limitancias que presentan las
actuales drogas empleadas en el tratamiento de la enfermedad de Chagas.
Nifurtimox, Benznidazol y otros fármacos empleados en contra el mal de Chagas y
algunos tipos de cánceres son capaces de producir radicales libres, los cuales en
presencia de oxígeno, generan a través de un ciclo redox, especies reactivas de oxígeno,
las cuales son sustancias altamente reactivas. El exceso de radicales libres puede generar
daño celular (estrés oxidativo), este daño ocurre sólo si la acción de estos radicales no es
remediada por los mecanismos de defensa presentes en cada organismo, como son los
antioxidantes. En el mismo orden de ideas, se utilizó la Resonancia de Espín Electrónico
para obtener información directa de las especies radicalarias.
Además el uso de la técnica de spin trapping permitió evidenciar especies reactivas de
oxígeno en medio biológico, durante la metabolización de los compuestos testeados.
Voltamperometría cíclica se empleó como una herramienta valiosa para evaluar el
mecanismo de reducción de ambas familias, donde fue posible identificar un mecanismo
de autoprotonación. Además resultó útil para la determinación parámetros de
significancia biológica.
Por otra parte, también se realizó la exploración de los confórmeros de mínima energía y
de las propiedades electrónicas empleando cálculos teóricos, específicamente teoría de
funcionales de la densidad (DFT). Estos indicaron que los derivados de nitrofurano
neutros tendían a adoptar una conformación plana estabilizada, mientras que los
radicalarios lo hacían a través del plegado de su cadena lateral respecto del anillo.
La familia de nitroindazoles también mostró que las conformaciones más estables
dependían de la influencia de los sustituyentes. La correlación de las propiedades
electrónicas con el potencial de pico catódico fue posible empleando el funcional híbrido
B3LYP/6-31G*+(d,p).
Finalmente, los ensayos biológicos mostraron que los derivados de nitrofurano resultan
ser activos contra T. cruzi cepa Dm28C, frente a sus formas morfológicas epimastigotes
y tripomastigote, encontrando valores de IC50 comparables y mejores a los reportados
para las drogas parentales / The present investigation show a chemical and biological study about two families of
nitro compounds: Nitrofurane and Nitroindazole derivatives, whith the target to obtain
the main characteristic about tripanocide action mechanism of its new potential drugs,
able to overcome the limitation the current treatment of Chagas disease.
Nifirtimox, benznidazol and other drugs used against Chagas disease and some of the
other types of cáncer disease are able to produce free radicals in which the presence of
the oxygen, create through the redox cicle a reactive oxygen species (ROS) they are
higly reactive subtances . The excess of the free radical can produce a celular damage
(oxidative stress) this damage ocurs only if the action of these free radicals is not
avoided by the action of antioxidant mechanism present in the organism.
In the same order we used the Electronic Spin Resonance to get direct information about
the free radicals.
Besides the technique use of Spin Trapping allowed to show the ractive oxygen species
of in a biological enviroment, during the methabolism of the testing compound.
We used a very important tool called Cyclic Voltametry in order to valued the reduction
mechanism of these compund. It was posible to identify an autoprotonation mechanism,
besides CV was used to obtain parameters of biologycal significance. In the other hand we also realized a conformational study and
the electronic properties using theorical calculations, specifically Density Functional
Theory (DFT).
This study indicates that the neutral nitrofurane derivatives adopt one plane stabilized
conformation, meanwhile the nitro radical structures adopted the stabilised conformation
trough the plication of the lateral chains respect to the nitrofurane ring.
The Nitroindazoles family showed that stabilised conformation depends on the
influence of the subtituents. The correlation of the electronic properties with the cathodic
peak potential was possbile using the Hybrid functional B3LYP/6-31G*+(d,p).
Finally the biologycal essays showed that the nitrofuranes derivates are actives against
T. cruzi strain Dm28C, obtained values of IC50, better and comparables with the parental
drugs / Conicyt
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Vliv oxidu dusnatého na průtok krve mozkem při neuronální aktivitě / Effect of nitric oxide on cerebral blood flow during neuronal activityStrnadová, Petra January 2011 (has links)
Name of the thesis Effect of nitric oxide on cerebral blood flow during neuronal activity Aim of the thesis The aim of this thesis is to determine whether the application of 7-nitroindazole, relatively specific inhibitor of neuronal nitric oxide synthase, affects the baseline blood pressure. Furthermore, to determine whether the application of the substance affects the baseline cerebral blood flow and whether it influences blood flow in brain during transcallosal stimulation with increasing frequency. Research method The research took place at the premises of the Institute of Physiology, Academy of Sciences of the Czech Republic. Experiments were carried out on laboratory albino Wistar rats. The group contained both experimental and control sample. General anesthesia was performed to rats, stimulating and sensing electrodes were implanted in epidural area of sensorimotor cortex and Laser Doppler flow probe was implanted into the contralateral hemisphere. A plastic catheter was applied in the carotid artery for measuring systemic blood pressure. In the first part of the experiment, we tested the effects of 7-nitroindazole on the systemic blood pressure. In the second part of the experiment, we investigated the effects of 7-nitroindazole on baseline cerebral blood flow. The third part of the...
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Farmakologické ovlivnění neurologického deficitu u modelu fokální mozkové ischémie u potkana / Neurological deficit after focal cerebral ischemia in rat - pharmacological interventionEliášová, Karolína January 2020 (has links)
Title: Neurological deficit after focal cerebral ischemia in rats - pharmacological intervention Objectives: The goal of the thesis was to determine the effect of 7-nitroindazole, a selective inhibitor of neuronal nitric oxide synthase, after focal ischemic stroke in rats. Methods: Twenty adult male Wistar rats were used in this experiment. The rats were randomly divided into four groups: ischemic stroke was given to half of them, the rest were sham operated. 10 animals were given 7-nitroindazole (25mg/kg) to protect neuronal ischemic brain damage. After a few weeks the rats were tested with a set of behavioral tests: Ladder rung walking test, Bar holding test, Rotarod test and Open field test. To evaluate the volume of brain damage the stereotactic method was used. The brain sections were cut and compared with atlas. This study was supported by Institute of Physiology, Academy of Sciences ČR in Prague. Results: The present results show that the 7-nitroindazole has no side effects on healthy rats. The long-term effect on rats after ischemic stroke was not proved. There were a few positive trends observed such as an increase of locomotor speed, increased explorative behaviour and better coordination outcome on RotaRod. On the other hand the brain tissue damage was bigger and the time of hanging in...
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