Diseño, síntesis y evaluación de compuestos con potencial actividad antimalárica. Preparación y aplicabilidad de imidazolinas en nuevos organocatalizadores bifuncionales

La tesis que a continuación se expone es una tesis multidisciplinar dado que abarca distintos ámbitos de la química orgánica. El primer capítulo se centra principalmente en el ámbito de la química médica, donde se discute el diseño, la síntesis y la evaluación biológica de cuatro familias de compuestos con potencial actividad antimalárica. Para el desarrollo de este trabajo se establece un convenio de colaboración con la empresa farmacéutica GSK, la cual lleva a cabo la evaluación biológica de todos los compuestos sintetizados. GSK ha publicado en una base de datos de acceso público los resultados obtenidos en screenings de compuestos que inhiben el crecimiento de P. falciparum. El desarrollo hit to lead de estos compuestos comienza con una exhaustiva búsqueda en dicha base de datos, eligiendo una serie de compuestos hits en base a sus propiedades farmacológicas y a su facilidad de síntesis. Una vez seleccionados los hits se procede al diseño de rutas sintéticas que permitan la obtención de las diferentes familias de compuestos de manera rápida y sencilla. En base a los resultados de actividad biológica se realiza un estudio SAR procediéndose, en caso necesario, a una reevaluación y rediseño de los compuestos obtenidos. El segundo capítulo está basado en el campo de la organocatálisis. En él se discute la incorporación de imidazolinas quirales para el desarrollo y síntesis de nuevos organocatalizadores bifuncionales de tipo tiourea y escuaramida. Una vez obtenidos los diferentes estereoisómeros de cada organocatalizador se estudia la eficacia y aplicabilidad de estos sistemas en catálisis asimétrica. Concretamente, se aborda un estudio de su potencial utilidad en la reacción enantioselectiva de Morita-Baylis-Hillman y en la reacción de Strecker. Por último y en forma de anexo se presenta el trabajo realizado durante la estancia doctoral en el grupo del Dr. Steven V. Ley de la universidad de Cambridge (Reino Unido). Durante este periodo en el Innovative Technology Centre (ITC), se ha desarrollado un trabajo basado en Flow Chemistry para la preparación de ciclopropanos funcionalizados a partir de diazo compuestos.The thesis that is exposed below is a multidisciplinary thesis that covers different areas of organic chemistry. The first chapter is focused mainly on the field of medical chemistry, which discusses the design, synthesis and biological evaluation of four families of compounds with potential antimalarial activity. For the development of this work, a collaboration agreement is established with the pharmaceutical company GSK, which carries out the biological evaluation of all the synthesized compounds. GSK has published in a public access database the results obtained in screenings of compounds that inhibit the growth of P. falciparum. The development hit to lead of these compounds begins with an exhaustive search in this database, choosing a series of hits compounds based on its pharmacological properties and its simplicity of synthesis. Once the hits are selected, we proceed to the design of synthetic routes that allow obtaining different families of compounds quickly and easily. Based on the results of biological activity, a SAR study is carried out and, if necessary, a re-evaluation and redesign of the compounds obtained. The second chapter is based on the field of organocatalysis. It discusses the incorporation of chiral imidazolines for the development and synthesis of new bifunctional thiourea/squaramide type organocatalysts. The utility of these systems is tested in asymmetric catalysis. For this purpose, all the diastereoisomers obtained are evaluated in order to determine the influence of stereochemistry in the different organocatalyst on enantioselective reactions, specifically in the Morita-Baylis-Hillman and in the Strecker reaction. Finally, in an annex, the work carried out during the doctoral stay in Dr. Steven V. Ley group of the University of Cambridge (United Kingdom) is discussed. During this period at the Innovative Technology Center (ITC), a work based on Flow Chemistry was developed for the preparation of functionalized cyclopropanes from diazo compounds

Cyclopropanation using flow-generated diazo compounds.

We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.We are grateful to Pfizer Worldwide Research and Development (CB, RJI and JMH), the Swiss National Science Foundation (DNT), CAPES (RL, no 9865/13-6) and the EPSRC (SVL, grant no EP/K0099494/1 and no EP/K039520/1) for financial support.This is the final published article, originally published in Organic & Biomolecular Chemistry, 2015,13, 2550-2554 DOI: 10.1039/C5OB00019

Design culture:from product to process. Building a network to develop design processes in Latin countries

The essay presents the results of a 2 years survey within 7 European and Latin American countries (Italy, Portugal, Spain, Argentina, Brazil, Chile, Mexico), focusing on the scientific and professional initiatives accomplished by universities and research centres in the field of designdriven innovation. The survey shows a growing interest towards the methodological aspects of design by the observed actors and urges the formation of a "Latin network" aimed at experimenting proper design processes for Latin countries' socio-cultural and productive systems. The basic idea is that design culture, considered as a process culture, has relevant advantages in the actual relationship between production and consumption: − Offering design a mediator's role between the crucial knowledge for sustainable development: economy, art/creativity, technology and humanities; − Producing a "phantasmagoric" capacity (the possibility to visualize and share what is immaterial and upcoming); − Mediating between the productive and consumption systems' interest

Comparison of epidemiology and clinical characteristics of infections by human parechovirus vs. those by enterovirus during the first month of life

Human parechoviruses (HPeV) have been recently recognized as important viral agents in paediatric infections. The aims of this study were to investigate the HPeV infection prevalence in infants <1 month in Spain and, secondly, to analyse the clinical and epidemiological characteristics of the infected patients compared with those infected by enterovirus (EV). Infants <1 month with neurological or systemic symptoms were included in a multicentre prospective study. EV and HPeV detection by RT-PCR and genotyping were performed in cerebrospinal fluids (CSF), sera or throat swabs. Out of the total of 84 infants studied during 2013, 32 were EV positive (38 %) and 9 HPeV positive (11 %). HPeV-3 was identified in eight cases and HPeV-5 in one. Mean age of HPeV-positive patients was 18 days. Diagnoses were fever without source (FWS) (67 %), clinical sepsis (22 %) and encephalitis (11 %). Leukocytes in blood and CSF were normal. Pleocytosis (p = 0.03) and meningitis (p = 0.001) were significantly more frequent in patients with EV infections than with HPeV. Conclusions: Although HPeV-3 infections were detected less frequently than EV, they still account for approximately 10 % of the cases analysed in infants younger than 1 month. HPeV-3 was mainly associated with FWS and without leukocytosis and pleocytosis in CSF. In these cases, HPeV screening is desirable to identify the aetiologic agent and prevent unnecessary treatment and prolonged hospitalization.This study was partially supported by a grant from the Spanish National Health Institute PI12-00904.S

Epidemiological and clinical characteristics of infants admitted to hospital due to human parechovirus infections: A prospective study in Spain

Incluye versión en castellano y en inglés.[ES] Introducción: Los parechovirus humanos (HPeV) son virus de la familia Picornaviridae, recientemente descritos, a los que se atribuyen cuadros de fiebre sin foco (FSF), sepsis clínica, gastroenteritis, meningitis o encefalitis fundamentalmente en lactantes pequeños. Nuestro objetivo fue describir la epidemiología y las características clínicas de las infecciones por HPeV en nuestro medio. Pacientes y métodos: Estudio multicéntrico prospectivo, llevado a cabo en 12 hospitales a nivel nacional, entre 2013-2015, en niños 3 meses. Todos los pacientes presentaron fiebre, el 45% irritabilidad, el 18,6% exantema y el 14% diarrea. No se observa ninguna alteración específica en las pruebas bioquímicas. El diagnóstico final más frecuente fue FSF (61%) seguido de sepsis clínica (29%). Aunque un 29% de los niños precisaron ingreso en cuidados intensivos, solo un paciente presentó secuelas. Conclusiones: Los HPeV circulan en nuestro país, afectando fundamentalmente a lactantes < 2 meses y se asocian a FSF y sepsis clínica, con un predominio en primavera y verano. Sería de interés implementar las técnicas moleculares de diagnóstico en todos los hospitales para reconocer y manejar adecuadamente estas infecciones. [EN] Introduction: Human parechovirus (HPeV) is one of the recently described picornaviridae viruses that have been associated with fever of unknown origin (FUO), clinical sepsis, gastroenteritis, meningitis, or encephalitis in very young infants. The aim of this study is to describe the epidemiology and clinical features of these viruses. Patients and methods: A prospective multicentre 3-year study was conducted in 12 hospitals in Spain. Out of 850 specimens examined, 47 were positive (5.52%), with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae. Results: Out of 850 specimens examined, 47 were positive (5.52%) for HPeV, with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae. Conclusions: HPeV circulates in our country, mainly during spring and summer, and affects young infants with a FUO and clinical sepsis. Molecular diagnostic techniques in all hospitals could help in improving the management of patients with these infections.Estudio financiado por el Fondo de Investigaciones Sanitarias: AES (PI12-00904).S

Comparison of epidemiology and clinical characteristics of infections by human parechovirus vs. those by enterovirus during the first month of life

Human parechoviruses (HPeV) have been recently recognized as important viral agents in paediatric infections. The aims of this study were to investigate the HPeV infection prevalence in infants <1 month in Spain and, secondly, to analyse the clinical and epidemiological characteristics of the infected patients compared with those infected by enterovirus (EV). Infants <1 month with neurological or systemic symptoms were included in a multicentre prospective study. EV and HPeV detection by RT-PCR and genotyping were performed in cerebrospinal fluids (CSF), sera or throat swabs. Out of the total of 84 infants studied during 2013, 32 were EV positive (38 %) and 9 HPeV positive (11 %). HPeV-3 was identified in eight cases and HPeV-5 in one. Mean age of HPeV-positive patients was 18 days. Diagnoses were fever without source (FWS) (67 %), clinical sepsis (22 %) and encephalitis (11 %). Leukocytes in blood and CSF were normal. Pleocytosis (p = 0.03) and meningitis (p = 0.001) were significantly more frequent in patients with EV infections than with HPeV. Conclusions: Although HPeV-3 infections were detected less frequently than EV, they still account for approximately 10 % of the cases analysed in infants younger than 1 month. HPeV-3 was mainly associated with FWS and without leukocytosis and pleocytosis in CSF. In these cases, HPeV screening is desirable to identify the aetiologic agent and prevent unnecessary treatment and prolonged hospitalization

Creación de un protocolo para el tratamiento con biológicos de la poliposis nasal

Treball Final de Grau en Medicina. Codi: MD1158. Curs acadèmic: 2019/2020La rinosinusitis crónica con poliposis nasal es un síndrome clínico, más que una enfermedad específica, cuya prevalencia está comprendida aproximadamente entre el 0,5 y 2,7% de la población general. Aunque no se considera una enfermedad curable, es posible su control con un tratamiento adecuado. Sin embargo, muchos pacientes no consiguen un óptimo control de sus síntomas a pesar de un tratamiento médico correcto o presentan altas tasas de recurrencia o recaída de los pólipos nasales tras la cirugía. El objetivo principal de este trabajo es crear un protocolo asistencial en el Servicio de Alergología del Hospital General Universitario de Castellón para lograr el control de la enfermedad con fármacos biológicos en los pacientes diagnosticados de poliposis nasal grave no controlada con tratamiento médico o recurrente tras la cirugía, reduciendo así el uso de glucocorticoides, evitando la realización de posibles cirugías y mejorando la calidad de vida. Tras realizar una búsqueda bibliográfica se han estudiado las indicaciones y el perfil de seguridad y eficacia de distintos fármacos biológicos utilizados en ensayos clínicos para el tratamiento de la poliposis nasal, se han elaborado dos protocolos para el manejo de dupilumab, el único aprobado actualmente para su uso en esta enfermedad, y mepolizumab.Chronic rhinosinusitis with nasal polyps is a clinical syndrome, rather than a specific disease, which prevalence is approximately between 0.5 and 2.7% of the general population. Although it is not cosidered a curable disease, its control is possible with adequate treatment. However, many patients do not achieve optimal control of their symptoms despite a correct medical treatment or have hight rates of recurrence or relapse of nasal polyps after surgery. The main goal of this work is to develop an assistance protocol in the Allergology Service of the “Hospital General Universitario de Castellón” in order to achieve control of the disease with biologics drugs in patients diagnosed with uncontrolled severe nasal polyposis despite medical treatment or surgery, thus reducing the use of glucocorticoids, avoiding possible surgeries and improving the quality of life of these patients. After an exhaustive bibliographic research, indications and the safety and efficacy profile of different biologic drugs used in clinical trials for the treatment of nasal polyposis have been studied, and two protocols for the management of dupilumab, the only one currently approved for its use in this disease, and mepolizumab, have been elaborated

Repeatability and agreement of swept-source optical coherence tomography and partial coherence interferometry biometers in myopes

Biometric measurements in the context of myopia are fundamental to detect eyes at risk of developing myopia and during the follow-up of patients with myopia control treatment. Thus, the accuracy of biometers has high clinical relevance

Design, synthesis and antimalarial evaluation of novel thiazole derivatives

As part of our medicinal chemistry program’s ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.M.C., A.C.C., J.A.M., N.R. and J.F.S.-C. thank the Ministerio de Ciencia e Innovación of Spain (research grant CTQ2011-27560) and the Consellería d’Educació, Investigació, Cultura i Esport de la Generalitat Valenciana (research grant PROMETEO/2013/027) for financial support