1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Análisis de viabilidad técnica-económica del parque eólico Altos de Peralta

RESUMEN La energia eolica se considera una forma indirecta de energia solar. Entre el 1 y 2% de la energia proveniente del sol se convierte en viento, debido al movimiento del aire ocasionado por el desigual calentamiento de la superficie terrestre. La energia cinetica del viento puede transformarse en energia util, tanto mecanica como electrica. La energia eolica, transformada en energia mecanica ha sido historicamente aprovechada, pero su uso para la generacion de energia electrica es mas reciente, en respuesta a la crisis del petroleo y a los impactos ambientales derivados del uso de combustibles. El objetivo principal de este trabajo es hacer un analisis de viabilidad desde un punto de vista tecnico y economico de un parque eolico situado en el municipio de Barasoain (Navarra). Desde el punto de vista tecnico se han estudiado los aspectos constructivos del parque considerando sus diferentes infraestructuras de obra civil y electrica asi como los niveles de recurso eolico. En el ambito economico y financiero se han analizado los aspectos y ratios mas relevantes que definen un proyecto de estas caracteristicas asi como el modelo de financiacion elegida basada en el Project- Finance. Entre las conclusiones mas destacadas de este proyecto cabe destacar la contribucion de la construccion del parque al desarrollo social y economico de la zona donde queda ubicado contribuyendo a la creacion de puestos de trabajo, tanto en la fase de construccion como de explotacion y una perfecta armonia con condicionantes medioambientales de la zona. El analisis tecnico realizado nos indica la viabilidad tecnica del parque tanto desde el punto de vista de recurso eolico como la idoneidad para poder evacuar la energia producida. Por otro lado, los resultados obtenidos cumplen perfectamente con los estandares requeridos por los financiadores de los parques y resultando ser muy atractivos para sus accionistas