Nuevas reacciones multicomponentes para la síntesis de derivados de piridina como agentes antineurodegenerativos potenciales

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Química Orgánica y Farmacéutica, leída el 15-06-2015Las principales conclusiones derivadas de esta tesis son las siguientes, 1. La reacción multicomponente catalizada por tricloruro de indio entre compuestos betadicarbonílicos, dimetilhidrazina, acroleínas y etanol proporciona derivados de 6etoxi1,4,5,6tetrahidropiridina. Esta transformación se acopló con un proceso de doble eliminación, sin necesidad de etapas de purificación intermedias, para dar lugar a un método de síntesis de piridinas 2,3disustitutidas que pudo adaptarse también a la preparación de varias familias de piridinas fusionadas. 2. La reacción tricomponente entre compuestos betadicarbonílicos, chalconas y acetato amónico en etanol a reflujo, en presencia de una cantidad catalítica de nitrato cérico amónico, conduce a 4,6diaril1,4dihidropiridinas. Estos compuestos mostraron una selectividad mejorada hacia el canal Cav1.3 neuronal en comparación con otras dihidropiridinas previamente conocidas y se comportan como agentes neuroprotectores frente a procesos de isquemia. 3. Una reacción similar entre betacetoamidas, chalconas y acetato amónico condujo al aislamiento directo de derivados de nicotinamida, a través de una secuencia reacción tricomponente, oxidación. 4. Se ha puesto a punto la síntesis de dihidropiridinas fusionadas y sus análogos oxigenados a través de reacciones tricomponentes de tipo Hantzsch entre malononitrilo, aldehídos aromáticos y pirazoles funcionalizados en C5 con estructura de lactama o amidina. Estos compuestos fueron diseñados por métodos computacionales como inhibidores de la enzima GSK3beta y se están estudiando como agentes anti Alzheimer. 5. Se han diseñado estructuras híbridas que contienen como fragmentos estructurales el nimodipino y un aza análogo de CGP37157 como agentes anti Alzheimer potenciales por estabilización de los niveles de calcio neuronal y mitocondrial a través de una aproximación multidiana. Estos compuestos se sintetizaron a través de una variante de la síntesis de Hantzsch de dihidropiridinas. También se han obtenido compuestos híbridos del mismo análogo de CGP37157 y ácido lipoico, un antioxidante capaz de atravesar la barrera hematoencefálica. Ambas familias de compuestos se están investigando como agentes anti Alzheimer. 6. Se ha desarrollado un método para la alquenilación oxidativa de arilsulfonamidas por medio de una reacción de activación CH catalizada por especies de a RuII.Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEunpu

One-Pot Access to a Library of Structurally Diverse Nicotinamide Derivatives via a Three-Component Formal Aza [3 + 3] Cycloaddition

The three-component formal [3 + 3] aza-annulation between chalcones, β-ketoamides, and ammonium acetate in the presence of CAN as a Lewis acid affords good to excellent yields of highly substituted nicotinamides or their fused derivatives. This transformation leads to the formation of one C–C and two C–N bonds in a single synthetic operation and involves up to five individual steps

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease

The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.R.L. thanks Instituto de Salud Carlos III co-financed by the European Regional Development's funds (FEDER) for a research contract under Miguel Servet Program (CP11/00165) and financial support from the European Commission-REA, People (Marie Curie Actions) FP7 under REA grant agreement n° PCIG11-GA-2012-322156; Spanish Ministry of Health (Instituto de Salud Carlos III) (grant PI14/00372); Bayer AG, From Targets to Drugs (grant 2015-03-1282) and Fundación FIPSE (grant 12-00001344-15). Ministerio de Economía y Competitividad, MINECO (grant CTQ-2015-68380-R) to J.C.M and grant SAF2015-63935R to M.G.L.; GW thanks Cancer Research UK (grant C9344/A10268), the BBSRC (grant BB/L01923X/1), the Bloomsbury Consortium and UCL School of Pharmacy for financial support. G.T. thanks Universidad Complutense for a predoctoral fellowship. P.M. thanks MECD for FPU fellowship (FPU13/03737). I. G. thanks UAM for a FPI fellowship. We also gratefully acknowledge the continued support of Instituto-Fundación Teófilo Hernando, Madrid, Spain.Peer Reviewe

Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease

Alzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca2+ homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2H-pyrazolo[3–b]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound 4g revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease.Ministerio de Educación, Cultura y Deporte(España)Universidad Autónoma de MadridUniversidad Complutense de MadridDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu

ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia

During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 μM) and veratridine in hippocampal slices (26% protection at 10 μM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 μM) and oxygen and glucose deprivation (76% protection at 10 μM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.Instituto de Salud Carlos IIIEuropean Commission-ERCMinisterio de Sanidad(España)Miguel ServetBayer A. G.Fundación FIPSEMinisterio de Economía, Comercio y Empresa(España)Ministerio de Economía, Cultura y Deporte(España)Fundación Tatiana Pérez de Guzmán el BuenoBioIbericaDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.Instituto de Salud Carlos IIIEuropean Regional Development's funds (FEDER)European Commission-REAMinisterio de Sanidad(España)Bayer AGFundación FIPSEMinisterio de Economía y Competitividad(España)Cancer Research UKBloomsbury ConsortiumUCL School of PharmacyUniversidad Complutense de MadridMinisterio de Educación, Cultura y Deporte(España)Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu

New 5‑Unsubstituted Dihydropyridines with Improved Ca_V1.3 Selectivity as Potential Neuroprotective Agents against Ischemic Injury

C₅-unsubstituted-C₆-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca²⁺ entry after a depolarizing stimulus and showed an improved Ca_v1.3/Ca_v1.2 selectivity in comparison with nifedipine. Furthermore, they were able to protect neuroblastoma cells against Ca²⁺ overload and oxidative stress models. Their selectivity ratio makes them highly interesting for the treatment of neurological disorders where Ca²⁺ dyshomeostasis and high levels of oxidative stress have been demonstrated. Furthermore, their low potency toward the cardiovascular channel subtype makes them safer by reducing their probable side effects, in comparison to classical 1,4-dihydropyridines. Some compounds afforded good protective profile in a postincubation model that simulates the real clinical situation of ictus patients, offering a therapeutic window of opportunity of great interest for patient recovery after a brain ischemic episode. Good activities were also found in acute ischemia/reperfusion models of oxygen and glucose deprivation

ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia

During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca²⁺ overload, such as toxicity induced by high K⁺ in the SH-SY5Y cell line (60% protection at 30 μM) and veratridine in hippocampal slices (26% protection at 10 μM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 μM) and oxygen and glucose deprivation (76% protection at 10 μM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine