RESUMEN
The aim of this tutorial review is to provide a general overview of processes, technologies and challenges in the production of pharmaceutical and bioactive compounds from food waste and lignocellulosic residues. Particular attention is given to benign-by-design processes instinctively devoted to environmental sustainability for the recovery of bioactive compounds from food waste as well as for the production of alcohols, acids, polyols, furans and aromatic compounds from lignocellulosic residues. At the same time, novel green synthetic routes for the production of active pharmaceutical ingredients and the development of novel bioactive compounds are discussed. Recent success industrial stories on the use of food waste and lignocellulosic residues for pharmaceutical and nutraceutical applications are also discussed.
Asunto(s)
Preparaciones Farmacéuticas , Eliminación de Residuos , Biomasa , Suplementos DietéticosRESUMEN
Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aß42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Aminoquinolinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/metabolismo , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Simulación de Dinámica Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismoRESUMEN
The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 µM), confirming the design rationale.
Asunto(s)
Ligandos , Fármacos Neuroprotectores/química , Extractos Vegetales/química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Anacardium/química , Anacardium/metabolismo , Sitios de Unión , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Diseño de Fármacos , Humanos , Lipopolisacáridos/farmacología , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Simulación de Dinámica Molecular , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Nueces/química , Nueces/metabolismo , Relación Estructura-Actividad , Tacrina/química , Tacrina/metabolismoRESUMEN
Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare neurodegenerative disorders. TSEs are characterized by the accumulation of prions (PrPSc) that represent pathological isoforms of the physiological cellular prion protein PrPC. Although the conversion of PrPC to PrPSc is still not completely understood, blocking this process may lead to develop new therapies. Here, we have generated a pharmacophore model, based on anti-prion molecules reported in literature to be effective in phenotypic assay. The model was used to conduct a virtual screen of commercial compound databases that selected a small library of ten compounds. These molecules were then screened in mouse neuroblastoma cell line chronically infected with prions (ScN2a) after excluding neurotoxicity. 1 has been identified as the therapeutic hit on the basis of the following evidence: chronic treatments of ScN2a cells using 1 eliminate PrPSc loaded in both Western blotting analysis and Real-Time Quaking-Induced Conversion (RT-QuIC) assay. We also proposed the mechanism of action of 1 by which it has the ability to bind PrPC and consequentially blocks prion conversion. Herein we describe the results of these efforts.
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Fenotiazinas/farmacología , Proteínas Priónicas/antagonistas & inhibidores , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Ratones , Modelos Moleculares , Estructura Molecular , Fenotiazinas/química , Proteínas Priónicas/aislamiento & purificación , Proteínas Priónicas/metabolismo , Relación Estructura-Actividad CuantitativaRESUMEN
In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug-resistant strains, T.â congolense, and a human cell line. The most potent activity was found against T.â b.â brucei, the causative agent of HAT. Shorter-chain derivatives 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.
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Adenosina Trifosfato/biosíntesis , Anacardium/química , Descubrimiento de Drogas , Mitocondrias/efectos de los fármacos , Extractos Vegetales/farmacología , Tripanocidas/química , Tripanocidas/uso terapéutico , Trypanosoma brucei brucei/efectos de los fármacos , Tripanosomiasis/tratamiento farmacológico , Animales , Humanos , Tripanocidas/farmacología , Trypanosoma brucei brucei/microbiologíaRESUMEN
Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3ß and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3ß, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 µM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.
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Enfermedad de Alzheimer/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas tau/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Fármacos del Sistema Nervioso Central/efectos adversos , Fármacos del Sistema Nervioso Central/química , Fármacos del Sistema Nervioso Central/farmacología , Dicroismo Circular , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Transferencia Resonante de Energía de Fluorescencia , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Células Hep G2 , Humanos , Microscopía de Fuerza Atómica , Terapia Molecular Dirigida/métodos , Ácido Ocadaico/toxicidad , Fosforilación/efectos de los fármacos , Ratas , Relación Estructura-Actividad , Porcinos , Tiazolidinedionas/química , Proteínas tau/antagonistas & inhibidoresRESUMEN
Therapy of prion diseases represents an extremely challenging effort for scientists working in the field. These challenges are epitomized by 20 years of failures in clinical trials and preclinical investigations. However, the discovery that misfolded proteins involved in other neurodegenerative diseases show a prion-like mechanism of spreading, is positively impacting the prion drug discovery field. Herein, we describe those efforts that have contributed to strengthen the drug discovery process in prion diseases. Accordingly, we analyze the historical course of clinical trials that have assessed the efficacy of several chemically unrelated repositioned drugs. Unfortunately, none of them resulted successful. Thus, alternative approaches aiming at identifying innovative drugs with a completely new mechanism of action, have been recently pursued. In this respect, the multifactorial nature of prion diseases provides a strong foundation to the development of small molecules directed to two or multiple pathological targets, critically involved in the intricate disease pathogenesis (i.e., multitarget compounds). Second, the fact that misfolded proteins can be considered not only as therapeutic target, but also as neuropathological hallmark, lends support to the development of theranostics, i.e., single molecules with concomitant therapeutic and diagnostic properties. Although nobody knows whether these innovative tools will be brought to clinical trials, and the process is certainly time-consuming and demanding, the rewards are well worth the effort.
Asunto(s)
Enfermedades por Prión/terapia , Animales , Antiinfecciosos/química , Antiinfecciosos/uso terapéutico , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Drogas en Investigación/uso terapéutico , HumanosRESUMEN
Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Descubrimiento de Drogas , Fármacos Neuroprotectores/farmacología , Humanos , Estructura Molecular , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/químicaRESUMEN
The Hippo pathway is an important organ size control signaling network and the major regulatory mechanism of cell-contact inhibition. Yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. Defects in the pathway can result in overgrowth phenotypes due to deregulation of stem-cell proliferation and apoptosis; members of the pathway are directly involved in cancer development. The pharmacological regulation of the pathway might be useful in cancer prevention, treatment, and regenerative medicine applications; currently, a few compounds can selectively modulate the pathway. In this review, we present an overview of the Hippo pathway, the sequence and structural analysis of YAP/TAZ, the known pharmacological modulators of the pathway, especially those targeting YAP/TAZ-TEAD interaction.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al ADN/metabolismo , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Medicina Regenerativa , Factores de Transcripción/metabolismo , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/química , Secuencia de Aminoácidos , Animales , Proteínas de Unión al ADN/química , Descubrimiento de Drogas , Vía de Señalización Hippo , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Terapia Molecular Dirigida/métodos , Neoplasias/metabolismo , Proteínas Nucleares/química , Fosfoproteínas/química , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/química , Medicina Regenerativa/métodos , Alineación de Secuencia , Transducción de Señal/efectos de los fármacos , Células Madre/metabolismo , Factores de Transcripción de Dominio TEA , Factores de Transcripción/química , Proteínas Señalizadoras YAPRESUMEN
Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3ß. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01)â µM and (14.67±0.78)â µM for BACE-1 and GSK-3ß, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Triazinas/química , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Barrera Hematoencefálica/metabolismo , Dominio Catalítico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Semivida , Lipopolisacáridos/toxicidad , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Simulación del Acoplamiento Molecular , Óxido Nítrico Sintasa de Tipo II/metabolismo , Unión Proteica , Ratas , Triazinas/metabolismo , Triazinas/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-ß (Aß) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aß. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Quinonas/química , Tacrina/química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Antioxidantes/química , Barrera Hematoencefálica/efectos de los fármacos , Técnicas de Química Sintética , Inhibidores de la Colinesterasa/química , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Células Hep G2/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Terapia Molecular Dirigida , Neuronas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas WistarRESUMEN
Prion diseases are fatal neurodegenerative and infectious disorders for which effective pharmacological tools are not yet available. This unmet challenge and the recently proposed interplay between prion diseases and Alzheimer's have led to a more urgent demand for new antiprion agents. Herein, we report the identification of a novel bifunctional diketopiperazine (DKP) derivative 1 d, which exhibits activity in the low micromolar range against prion replication in ScGT1 cells, while showing low cytotoxicity. Supported by properly addressed molecular modeling studies, we hypothesized that a planar conformation is the major determinant for activity in this class of compounds. Moreover, studies aimed at assessing the mechanism-of-action at the molecular level showed that 1 d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrP(Sc))-like form. This investigation suggests that DKP based antiprion compounds can serve as a promising lead scaffold in developing new drugs to combat prion diseases.
Asunto(s)
Dicetopiperazinas/química , Priones/antagonistas & inhibidores , Línea Celular , Dicetopiperazinas/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Enfermedades por Prión/tratamiento farmacológico , Priones/genética , Priones/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéuticoAsunto(s)
Alcanos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Etilaminas/uso terapéutico , Alcanos/síntesis química , Alcanos/química , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Etilaminas/síntesis química , Etilaminas/química , Humanos , Ratones , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Heterodimers 4 and 5 were effective inhibitors of acetylcholinesterase (AChE) activity and AChE-induced amyloid-beta (A beta) aggregation. The peculiar biological profile of 4 can be relevant in studying the molecular basis underlying the nonclassical action of AChE and in addressing the question whether AChE inhibitors can affect the neurotoxic cascade leading to Alzheimer's disease. Compound 4 emerged as the most potent heterodimer so far available to inhibit AChE-induced A beta aggregation.