153 research outputs found

    Desarrollo de modelos de predicción de emergencia de malas hierbas en condiciones de secano

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    Las malas hierbas son el principal desafío en la protección de cultivos ya que pueden llegar a causar pérdidas potenciales de más del 30% del rendimiento total. Además, la capacidad de adaptación a los métodos de control, incluyendo la aparición de individuos resistentes a herbicidas, está dificultando su manejo. Por ello, es necesario incrementar el conocimiento de la biología de las malas hierbas. Un punto vulnerable, particularmente en malas hierbas anuales de semilla pequeña, es el momento de su emergencia ya que dependen de las escasas reservas de la semilla hasta el momento en el que consiga realizar la fotosíntesis. De este modo, los métodos de control aplicados en estos estadios obtendrían mayores eficacias. Por consiguiente, el conocimiento del momento de emergencia de las malas hierbas facilitaría su manejo, especialmente en el caso de malas hierbas preocupantes como Avena sterilis ssp. ludoviciana (Durieu) Gillet & Magne, Centaurea diluta Aiton, Lolium rigidum Gaudin y las tres especies de Phalaris (Phalaris brachystachys Link, Phalaris minor Retz y Phalaris paradoxa L). Por un lado, L. rigidum y A. sterilis ssp. ludoviciana son malas hierbas problemáticas en todo el mundo, y en los últimos años se ha incrementado la dificultad para controlarlas debido a la aparición de biotipos resistentes. Por otro lado, C. diluta y las tres especies del género Phalaris son malas hierbas especialmente preocupantes en el sur de España, de las cuales es necesario incrementar su estudio para poder establecer estrategias óptimas de manejo. Para incrementar el conocimiento de la biología de L. rigidum, C. diluta y A. sterilis, se estableció un experimento en condiciones de campo en distintas localidades repartidas por España. El número de localidades varió entre 9 y 11 localidades, dependiendo de la especie. En cada localidad se sembraron un total de 400 semillas por especie y localidad, con cuatro repeticiones. La siembra se realizó en el otoño de 2016 y se monitoreó la emergencia durante dos campañas agrícolas en condiciones de secano. Por otro lado, para estudiar la emergencia de las tres especies de Phalaris, se realizaron experimentos de campo en dos localidades del sur de España durante dos (2006/07 y 2007/08) y tres (de 2005/06 a 2007/08) campañas agrícolas. En ambas localidades, se embraron 500 semillas de cada especie de Phalaris en cada campaña agrícola, simulando las condiciones de los campos de cereales de secano. La emergencia de L. rigidum total respecto al total de las semillas sembradas fue del 59% en el primer año y de un 9% en el segundo año. Su emergencia varió en función de la localidad, comenzando entre los 5 y los 16 días después de la siembra (DAS) y terminando entre los 40 y 110 DAS. Por otro lado, la emergencia de C. diluta fue del 39% en el primer año y de un 11% en el segundo año. En ambos años, el principal pico de emergencia C. diluta se produjo aproximadamente a los 45 DAS. Mientras que para el caso de A. sterilis ssp. ludoviciana el porcentaje de emergencia fue del 30% durante la primera campaña agrícola y del 21% durante la segunda. En ambas temporadas, el principal pico de emergencia se produjo entre noviembre y febrero. Respecto a la emergencia de las tres especies de Phalaris, el periodo de emergencia duró entre 31 y 48 DAS, mostrando dos picos principales. Además de estudiar la emergencia, estos ensayos sirvieron para desarrollar modelos para predecir la emergencia de las seis especies estudiadas y para validar lo modelos previamente publicados de L. rigidum (Izquierdo et al. 2013) y A. sterilis ssp. ludoviciana (Leguizamón et al. 2005). En ambos casos, los modelos nuevos obtuvieron mayor precisión que los modelos previamente publicados. El nuevo modelo de L. rigidum se basó en tres puntos cardinales que se establecieron en 5.8 ºC, 11.5 ºC y 20.6ºC para la temperatura base (Tb), optima (To) y techo (Tc), respectivamente. Además, el modelo basado en el tiempo hidrotérmico (HTT) no mejoró significativamente el modelo basados únicamente en el tiempo térmico (TT). La precisión de los modelos nuevos fue mejor en las localidades del norte que en las del sur. Por ello, se desarrollaron modelos específicos para el norte y sur. El modelo desarrollado para las localidades del norte funcionó muy bien, pero el modelo del sur necesita mejorar su precisión. Estos trabajos revelan que, en lo que respecta a esta especie de mala hierba, probablemente deban desarrollarse modelos diferentes para las distintas condiciones climáticas. Respecto al modelo de C. diluta, la función Weibull de tres parámetros fue la que mejor describió su emergencia. Se desarrollaron modelos de emergencia basados en TT y HTT que mostraron un alto grado de precisión, como demuestran los valores del error medio cuadrático (RMSE) de 10.8 y 10.7, respectivamente. Para estos modelos se establecieron los tres puntos cardinales en 0.5ºC, 10.0 ºC y 35 ºC para las Tb, To y Tc; mientras que el potencial hídrico base (Ψb) se estimó en -0.5 MPa. El modelo de A. sterilis ssp. ludoviciana también utilizó tres temperaturas cardinales para estimar el TT. Los tres puntos cardinales se establecieron en -1.0 ºC, 5.8ºC y 18.0ºC para las Tb, To y Tc, mientras que Ψb se estableció en -0.2 MPa para la estimación de la HTT. Por último, los modelos para las tres especies de Phalaris, tanto los modelos paramétricos como no paramétricos, se establecieron en base a tres puntos cardinales. Las Tb, To y Tc se establecieron entre -1 °C y 1 °C, entre 9.8 °C y 11.8 °C y entre 21.2 °C y 23.4 °C, respectivamente; mientras que el Ψb se estimó entre -1 y -1.1 MPa. Además de desarrollarse modelos nuevos para cada especie, éstos se validaron en ensayos independientes. Se obtuvo un ajuste adecuado (RMSE<15) en 2 de las 2 situaciones testadas para C. diluta y 5 de 8 para A. sterilis ssp. ludoviciana. Mientras que los modelos paramétricos y los no paramétricos de las tres especies de Phalaris obtuvieron resultados similares y fueron validados con éxito en 12 de los 15 experimentos independientes. Adicionalmente a estos ensayos, se desarrolló una aplicación, llamada MalertappUS (https://malertappus.es/), capaz de predecir la emergencia implementando los nuevos modelos desarrollados para A. sterilis ssp. ludoviciana, C. diluta, L. rigidum, P. brachystachys, P. minor y P. paradoxa. Además, se añadieron los modelos de dos especies adicionales (Papaver rhoeas L. y Bromus diandrus Roth). Utilizando los datos proporcionados por esta aplicación, se validaron los modelos de estas ocho especies durante dos campañas agrícolas (2019/20 y 2020/21) en seis y nueve localidades respectivamente. Las especies que obtuvieron resultados suficientemente robustos para su uso fueron: C. diluta con 93% de éxito, B. diandrus con un 86%, L. rigidum con un 85%, P. rhoeas con un 77%, P. paradoxa con un 71% y A. sterilis ssp. ludoviciana con un 53%.Weeds are the main challenge in crop protection because they are able to reduce the potential yield losses in more than 30%. In addition, their ability to adapt to the different control methods, including the herbicide resistant, is increasing the difficulty to establish strategies to manage them. Therefore, it is necessary to study their biology in order to achieve an integrate weed management. The seedling stages, particularly in species with small seeds, is the main vulnerable moment for most weeds due to in fact that the scarce seed reserves are empty and the seedling has to start to perform the photosynthetic activity. Thus, control methods applied at these stages would be the most effective. Consequently, the knowledge of the weed emergence pattern would facilitate their management, especially in the case of troublesome weeds such as Avena sterilis ssp. ludoviciana (Durieu) Gillet & Magne, Centaurea diluta Aiton, Lolium rigidum Gaudin and three Phalaris species (Phalaris brachystachys Link, Phalaris minor Retz y Phalaris paradoxa L). On the one hand, L. rigidum and A. sterilis ssp. ludoviciana are problematic weeds worldwide that the difficulty of their control has been increased due to the apparition of resistant biotypes. On the other hand, C. diluta and the three species of the genus Phalaris are especially troublesome weeds in southern Spain, which need to be further studied in order to establish optimal management strategies. To increase the biology knowledge of L. rigidum, C. diluta and A. sterilis ssp. ludoviciana, a field conditions experiment was established in different sites throughout Spain. The number of sites varied between 9 and 11 locations, depending on the species. A total of 400 seeds of each species were sown in each sites with four replicates. The sowing was carried out in the autumn of 2016 and their emergence was monitored during two growing seasons under rainfed conditions. On the other hand, in order to study the emergence of the three Phalaris species, field experiments were conducted in two different sites, placed in southern Spain, during two (2006/07 and 2007/08) and three (from 2005/06 to 2007/08) growing season. In both sites, 500 seeds of each Phalaris species were sown in each growing season, simulating the conditions of rainfed cereal fields. The total emergence of L. rigidum from total sowed seeds was 59% in the first season and 9% in the second season. Its emergence varied according to the sites, starting between 5 and 16 days after sowing (DAS) and ending between 40 and 110 DAS. On the other hand, emergence of C. diluta was 39% in the first season and 11% in the second. In both season, the main peak of C. diluta emergence occurred at 45 DAS. A. sterilis ssp ludoviciana reached up the 30% of emergence in the first season and 21% in the second; And, in both seasons, the main peak of emergence occurred between November and February. Regarding the emergence of the three Phalaris species, the emergence period lasted between 31 and 48 DAS, showing two main peaks. Despite of studying emergence, these trials were used to develop weed emergence models of the six studied species and, also, to validate previously published models for L. rigidum (Izquierdo et al., 2013) and A. sterilis ssp ludoviciana (Leguizamón et al., 2005). In both cases, the new models obtained higher accuracy than the models previously published. The new L. rigidum model was based on three cardinal points that were set at 5.8ºC, 11.5 ºC and 20.6 ºC for base (Tb), optimum (To) and ceiling (Tc) temperature, respectively. On the other hand, the model based on hydrothermal time (HTT) did not significantly improve the models based on thermal time (TT). The accuracy of the new models performed better in northern locations than in southern locations. Therefore, specific models were developed for the north and south. The model developed for the northern locations performed very well, but the southern one needs to improve its accuracy. This study reveals that, for this weed species, different models should probably be developed for different climatic conditions. Regarding the C. diluta model, the three-parameter Weibull function best described seedling emergence of C. diluta. Emergence models were developed based on TT and HTT and showed high predictability, as evidenced by root mean square error (RMSE) values of 10.8 and 10.7, respectively. The three cardinal points were established for TT and HHT at 0.5 ºC, 10 ºC and 35 ºC for Tb, To and Tc, while base water potential (Ψb) was estimated at -0.5MPa. The A. sterilis ssp ludoviciana model also used three cardinal temperatures to estimate TT. The three cardinal points were set at -1.0, 5.8 and 18.0 C for Tb, To and Tc, while Ψb was set at -0.2 MPa for HTT estimation. Finally, the models for the three Phalaris species established three cardinal points for the parametric and non-parametric models were set between -1 °C and 1 °C for Tb, between 9.8 °C and 11.8 °C for To and between 21.2 °C and 23.4 °C for Tc; while Ψb was estimated between -1 and -1.1 MPa. In addition, these new models were validated at different independent situations. An adequate fit (RMSE<15) was obtained in 2 of the 2 situations tested for C. diluta and 5 of 8 for A. sterilis ssp ludoviciana. While parametric and non-parametric models for the three Phalaris species obtained similar results and were successfully validated in 12 of the 15 independent experiments. Despite of these trials, a new web application to predict the weed emergence was developed. This application is called MalertappUS and is available at https://malertappus.es. MalertappUS is able to predict the weed emergence implementing the new developed models for A. sterilis ssp. ludoviciana, C. diluta, L. rigidum, P. brachystachys, P. minor and P. paradoxa. Moreover, the models of two additional species (Papaver rhoeas L. and Bromus diandrus Roth) were also added. Using the data provided by this application, the models for these eight species were validated during two growing seasons (2019/20 and 2020/21) at six and nine locations, respectively. The species that obtained sufficiently robust results for their use were: C. diluta with 93% of success, B. diandrus with 86%, L. rigidum with 85%, P. rhoeas with 77%, P. paradoxa with 71% and A. sterilis ssp. ludoviciana with 53%

    Predicting seedling emergence of three canarygrass (Phalaris) species under semi-arid conditions using parametric and non-parametric models

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    The Phalaris genus includes annual weed species such as short-spiked canarygrass (Phalaris brachystachys Link.), little-seed canarygrass (Phalaris minor Retz.) and hood canarygrass (Phalaris paradoxa L.), which are especially problematic in Spain; as such, there is a need to develop models to predict the timing of their emergence. Field experiments were conducted at two different locations during two (2006/07 and 2007/08) and three (from 2005/06 to 2007/08) growing seasons. In both locations, 500 seeds of each Phalaris species were sown each growing season, simulating rain-fed cereal field conditions. In addition, the models were validated with three, four and eight independent experiments for P. brachystachys, P. minor and P. paradoxa, respectively. The emergence period of the three Phalaris species lasted between 31 and 48 days after sowing (DAS), showing two main flushes. The three cardinal points for parametric and non-parametric models were established to be between −1 ◦C and 1 ◦C for base temperature, between 9.8 ◦C and 11.8 ◦C for optimal temperature and between 21.2 ◦C and 23.4 ◦C for ceiling temperature; base water potential was estimated to be between −1 and −1.1 MPa. Both parametric and non-parametric models obtained similar results and were successfully validated in 12 out of 15 independent experiments.This research and the APC were both funded by CATEDRA ADAMA. European Regional Development Funds (FEDER) and the Spanish Ministry of Economy and Competitiveness funds (AGL2005-0405) also supported data collection between 2005 and 200

    Paraneoplastic pemphigus: initial manifestation of lung cancer

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    O uso de TIC digital por professores e sua adaptação aos modelos atuais

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    In this article, we present a study intended to verify the importance and adequacy of the use of information and communication technologies (ICT) in the school environment for their greater adaptation to reality. This issue is reflected in the general objective, focused on determining the use made by teaching staff of new technologies in classrooms and their impact on the teaching-learning process of their students, taking into account the weaknesses present in the pedagogical foundations put forward by some of the most recent studies on the use and optimization of digital ICT in the classroom. The study has a quantitative, non-experimental, descriptive, and correlational design. In the study, 100 teachers of Compulsory Secondary Education (ESO) in institutes of Coimbra (Portugal) participated. An put forward questionnaire was developed to determine the use and frequency of new technologies in the classroom by the teaching staff. The data collected in the questionnaires were analyzed using the Statistical Package for the Social Sciences. The main conclusions confirm that there is still a need for an in-depth debate on the epistemological foundations implicit in the use of the new digital tools, and on whether ICTs are an adequate teaching tool, according to the current educational models, in time-cost terms for better student achievement and academic success. In fact, the debate is more than ever alive; new technologies have been increasingly implemented in the educational field during COVID-19 pandemics. This situation has even implied the suspension of in-person teaching activities that have led to the use of new technologies in the classroom immediately.En el artículo presentamos un estudio en el que se pretende constatar la importancia y adecuación sobre el uso de las tecnologías de la información y de la comunicación (TIC) en el ámbito escolar para su mayor adecuación a la realidad. Esta cuestión queda plasmada en el objetivo general, centrado en determinar el uso que hace el personal docente de las tecnologías digitales, su adecuación a los modelos vigentes en las aulas y su repercusión en el proceso de enseñanza-aprendizaje de sus estudiantes, teniendo en cuenta las debilidades presentes en los fundamentos pedagógicos esgrimidos por algunos de los más recientes estudios sobre el uso y optimización de las TIC digitales en el aula. El estudio se enmarca en un diseño de corte cuantitativo, no experimental, descriptivo y correlacional. En el estudio participaron 100 docentes de Educación Secundaria Obligatoria (ESO) en institutos de Coímbra (Portugal). Se elaboró un cuestionario creado ad hoc para conocer el uso y frecuencia de las nuevas tecnologías en el aula por parte del personal docente. Los datos recogidos en los cuestionarios fueron analizados a través del paquete estadístico Statistical Package for the Social Sciences. Las principales conclusiones confirman que es necesario aún un debate profundo sobre los fundamentos epistemológicos implícitos en el uso de las nuevas herramientas digitales; sobre si las TIC son una herramienta docente adecuada, acorde a los modelos educativos del presente, en términos tiempo-coste para un mejor rendimiento y éxito académico del estudiantado. De hecho, el debate está más vivo que nunca, las nuevas tecnologías se han insertado, cada vez más, en el ámbito educativo, durante el COVID-19, lo cual ha implicado, incluso, la suspensión de actividades docentes presenciales que han conllevado el uso de las nuevas tecnologías en el aula de forma inmediataApresentamos nesse artigo um estudo no qual se pretende verificar a importância e a adequação do uso das tecnologias de informação e comunicação (TIC) no ambiente escolar para a sua maior adaptação à realidade. Esta questão está refletida no objetivo geral da mesma, centrada em determinar a utilização que o corpo docente faz das novas tecnologias em sala de aula e o seu impacto no processo de ensino-aprendizagem dos estudantes, considerando as fragilidades presentes nas bases pedagógicas de alguns dos estudos mais recentes sobre a utilização e otimização das TICs digitais na sala de aula. O estudo está enquadrado em um desenho quantitativo, não experimental, descritivo e correlacional. No estudo, 100 professores do Ensino Secundário Obrigatório (ESO) participaram em institutos de Coimbra (Portugal). Foi elaborado um questionário criado ad hoc para conhecer a utilização e frequência das novas tecnologias em sala de aula pelo corpo docente. Os dados coletados nos questionários foram analisados por meio do sistema estatístico Statistical Package for the Social Sciences. As principais conclusões confirmam que ainda é necessário um debate aprofundado sobre os fundamentos epistemológicos implícitos na utilização das novas ferramentas digitais, questionando se as TIC são um instrumento de ensino adequado, de acordo com os modelos educacionais da atualidade, em termos de tempo-custo, para um melhor desempenho dos estudantes e sucesso acadêmico. Na verdade, o debate está mais atual que nunca, as novas tecnologias foram cada vez mais inseridas no campo educacional, durante o COVID-19, o que implicou, inclusive, a suspensão das atividades de ensino presencial, que levaram ao uso imediato de novas tecnologias na sala de aul

    Estado del arte del proyecto

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    Colombia enfrenta varios desafíos para asegurar un suministro de energía confiable, asequible y amigable con el medio ambiente. Persistentemente bajas tasas de reserva de producción en petróleo y gas, junto con el avance del cambio climático, están poniendo en riesgo el sistema energético del país fuertemente dependiente de la energía hidroeléctrica, la electricidad de Colombia, se volverá más vulnerable con patrones climáticos extremos como El Niño. Este trabajo tiene por objeto el desarrollo de un modelo de negocio que incentive la realización de proyectos con integración de generación distribuida e implementación de infraestructura avanzada AMI, buscando obtener resultados significativos en lo que respecta a la calidad del servicio, aplanamiento de la curva de demanda, estabilidad de la red, identificación y reducción de pérdidas de cara al operador de red como actor activo de la negociación, una mejor percepción en la calidad del servicio a precios más exequibles por parte del usuario final y la recuperación de la inversión con la respectiva utilidad por parte del inversionista. Así mismo se busca realizar un análisis del potencial de la generación solar fotovoltaica a nivel doméstico y demostrar cómo el país puede beneficiarse de la tendencia mundial del uso creciente de tecnologías de energía renovable y su mejora en el rendimiento, la eficiencia y la competitividad de costos, así mismo se evalúa el impacto de la integración de los infraestructura de medida avanzada respecto a los resultados esperados por los entidades que las promocionan así como los actores que interventen en el modelo comercial planteado. Para lógralo se busca plantear una alianza estratégica entre el operador de red ENERGUAVIARE S.A. E.S.P. quien presta sus servicios de distribución y comercialización de energía en la Amazonia Colombiana y un inversionista privado, de tal modo, que el operador de red no requiera inversión en CAPEX, la cual será realizada por un actor privado quien además de ayudar a dar cumplimiento a las legislaciones y resoluciones existentes, facilitara el mejoramiento de los procesos propios del ejercicio comercial de la energía a cambio de pagos mensuales por cada usuarios intervenido, que permitirá al inversionista recuperar su inversión y obtener la utilidad pertinente, por ultimo y no menos importante de cara al usuario final se lograra una disminución significativa en la factura, mayor interacción en los procesos relacionados con el servicio público y la percepción de mayor eficiencia. La investigación inicia con el desarrollo de una revisión bibliográfica de los modelos de negocio existentes y casos de éxito que promueven la inclusión exitosa de recursos energéticos distribuidos en conexión a la red eléctrica, así como la inversión en la reconversión tecnológica de los equipos con los que cuenta las redes eléctricas de determinada región, se procede con la caracterización de la población objetivo, a través de herramientas y métodos gráficos que permiten realizar una clasificación de acuerdo al punto de vista económico y social, después se seleccionan los componentes requeridos para el desarrollo de un modelo económico-energético que considerara este tipo de recursos en proyectos de uso final, para así establecer los criterios de diseños, posteriormente, se proponen pasos metodológicos que permiten el planteamiento y la evaluación de estos tipos de proyectos conforme a la obtención de un diagrama de flujo descriptivo, el cual servirá como herramienta principal para determinar la factibilidad del modelo

    Modeling emergence of sterile oat (Avena sterilis ssp. ludoviciana) under semiarid conditions

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    Winter wild oat [Avena sterilisssp. ludoviciana (Durieu) Gillet & Magne; referred to as A. sterilis here] is one of the major weed species of the Avena genus, given its high competitive ability to infest cereal crops worldwide, with special concern in Spain. A nine-location field experiment was established across Spain where a total of 400 A. sterilis seeds per location were sowed in four replicates in autumn 2016 to monitor the emergence during two growing seasons in dryland conditions. The data were used to test the prediction ability of previously published thermal (TT) and hydrothermal time (HTT) models and to develop new models, if required. Overall, the average percentage of emergence was 30% during the first season and 21% during the second season. In both seasons, the main emergence flush occurred between November and February. According to the phenological stage, A. sterilis achieved the tillering earlier in southern sites, between November 25 and the end of December, compared with northern sites, where this stage was reached at the end of January. The newly developed model described the emergence with precision, using three cardinal temperatures to estimate the TT. The three car dinal points were established at −1.0, 5.8, and 18.0 C for base (Tb), optimum (To), and ceiling temperature (Tc), while the base water potential (Ψb) was established at −0.2 MPa for the HTT estimation. This study contributes to improving prediction of the emergence of A. sterilis and provides knowledge for decision support systems (DSS) for the control of this weed.We would like to thank first the funding institutions, Cátedra Adama and the Spanish Weed Science Society (SEMh), with special mention of Cátedra Adama, which financed the article publishing charges. Also, JT acknowledges support from the Spanish Ministry of Science, Innovation and Universities (grant Ramon y Cajal RYC2018-023866-I). We also want to thank the students and the technicians that have helped with the fieldwork for this experiment in different sites, without whose help data col lection would have been more difficult. No conflicts of interest have been declared

    Should emergence models for Lolium rigidum be changed throughout climatic conditions? The case of Spain

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    Lolium rigidum Gaudin is a troublesome weed worldwide, and its distribution may increase due to climate change. It has become resistant to several herbicides and, therefore, its control is problematic. On the other hand, its seed biology, with little dormancy and short-term viability, can play a major role in reducing its seed bank, which would improve control of this weed. For this reason, knowledge of the emergence patterns of this species entails improvements for its management. In this work seeds from one population of L. rigidum, collected in Northeastern Spain, were distributed and sown in 11 sites across Spain, and its emergence was followed every 2–7 days for two growing seasons (2016-17 and 2017–18). These emergence sequences were compared with previously published thermal time and hydrothermal time based models, and new models were developed afterwards. The hydrothermal time based model did not significantly improve models based solely on thermal time. The accuracy of these newly developed models varied from site to site, but in general, they worked better for Northern locations than for Southern locations. Thus, the experimental sites were split between North and South, and specific models for each region were developed. The model developed for Northern sites worked very well, but the one for Southern sites needs improvement. This works reveals that, with regard to this weed species, probably different models should be developed for different climatic conditions. The model developed with data from Northern sites should be validated with local populations, while the one developed with data from Southern sites will probably need to be revised or newly developed with data from more Southern populations.The group from the University of Lleida-Agrotecnio would also like to thank the Spanish Goverment for partial funding, through project AGL2017-83325-C4-2-R (AEI/FEDER/UE)

    Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3

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    Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-ca​rboxamide(THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,​4′-thieno[3,2-c]pyran](Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice
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