A5107974946- Cholinesterase and Neurodegenerative Diseases
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Synthesis and biological activity
- Synthesis and Biological Evaluation
- Chemical Synthesis and Analysis
- Phosphodiesterase function and regulation
- Wnt/β-catenin signaling in development and cancer
- Nicotinic Acetylcholine Receptors Study
- HIV/AIDS drug development and treatment
- Synthesis and Characterization of Heterocyclic Compounds
- Peptidase Inhibition and Analysis
- Cytomegalovirus and herpesvirus research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Click Chemistry and Applications
- Cancer therapeutics and mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- Quinazolinone synthesis and applications
- Chemical synthesis and alkaloids
- Medicinal Plants and Neuroprotection
- Cannabis and Cannabinoid Research
- Receptor Mechanisms and Signaling
- Crystallography and molecular interactions
Instituto de Química Médica
2015-2025
Consejo Superior de Investigaciones Científicas
2013-2024
Ação Educativa
2024
Universidad Complutense de Madrid
1991-2023
Centro de Investigaciones Biológicas Margarita Salas
1989-2020
Hospital Universitario Virgen del Rocío
2011
Universidad de La Laguna
1981-2008
Centro de Biología Molecular Severo Ochoa
2002-2005
Universidad Autónoma de Madrid
2002-2005
Universitat de Barcelona
2005
Glycogen synthase kinase 3 β (GSK-3β) has a central role in Alzheimer's disease (AD). Selective inhibitors which avoid τ hyperphosphorylation may represent an effective therapeutical approach to the AD pharmacotherapy and other neurodegenerative disorders. Here, we describe synthesis, biological evaluation, SAR of small heterocyclic thiadiazolidinones (TDZD) as first non-ATP competitive inhibitor GSK-3β. Their synthesis is based on reactivity sulfenyl chlorides. In GSK-3β assays, TDZD...
Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases decrease β-amyloid (Aβ) levels by complexation of redox-active metals, respectively. In this work, novel tacrine−8-hydroxyquinoline hybrids have been designed, synthesized, evaluated as potential multifunctional for the treatment Alzheimer's disease. At nano- subnanomolar concentrations they human acetyl- butyrylcholinesterase (AChE BuChE), being more potent than tacrine. They also displace...
By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, evaluated biologically. The tacrine fragment was selected its inhibition cholinesterases, flavonoid scaffold derived from 4-oxo-4H -chromene chosen radical capture β-secretase 1 (BACE-1) inhibitory activities. At nano- picomolar concentrations, inhibit human acetyl- butyrylcholinesterase (h-AChE...
Tacrine and melatonin are well-known drugs with activities as an acetylcholinesterase (AChE) inhibitor free radical scavenger, respectively. In this work, we report new hybrids of both that display higher in vitro properties than the sum their parts. As selective inhibitors human AChE, IC50 values range from sub-nanomolar to picomolar. They exhibit a oxygen absorbance capacity does predicted be able cross blood−brain barrier reach targets central nervous system.
Tacrine-melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer's disease. These compounds may simultaneously palliate intellectual deficits protect the brain against both beta-amyloid (A beta) peptide oxidative stress. They show improved cholinergic antioxidant properties, are more potent selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. also capture free radicals better melatonin. Molecular modeling studies that these...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting muscle wasting, paralysis, death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion sporadic suggests new therapeutic targets pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive onset progression may result...
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 phosphorylating kinase GSK-3β and aggregation process. On basis this consideration on our interest in multitarget paradigms AD, we report discovery 2,4-thiazolidinedione derivatives endowed with such a profile. 28 30 displayed micromolar IC50 values toward GSK-3β, together capacity inhibiting AcPHF6...
The 2,4-disubstituted thiadiazolidinones (TDZD) are described as the first ATP-noncompetitive GSK-3 inhibitors. Following an SAR study about TDZD, different structural modifications in heterocyclic ring aimed to test influence of each heteroatom on biological here reported here. Various compounds such hydantoins, dithiazolidindiones, rhodanines, maleimides, and triazoles were synthesized screened After extensive among these families, TDZDs have been revealed a privileged scaffold for...
Novel multifunctional compounds have been designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease (AD). With an l-glutamic moiety a suitable biocompatible linker, three pharmacophoric groups were joined: (1) N-benzylpiperidine fragment selected to inhibit acetylcholinesterase by interacting with catalytic active site (CAS), (2) N-protecting group amino acid, capable (AChE)-peripheral anionic (PAS) protecting neurons against oxidative stress, (3)...
Glycogen synthase kinase 3 (GSK-3) is an important drug target for human severe unmet diseases. Discovery and/or design of allosteric modulators are gaining importance in this field not only the increased selectivity kind compounds but also subtle modulation target. This last point utmost GSK-3 inhibition as a therapeutic approach. activity completely necessary life, and aberrant overactivity found pathologies should be inhibited with its inhibitors treatment. We performed here search...
Background Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP many cell types. This cyclic nucleotide key signal transduction wide variety cellular responses. In the brain, has been implicated learning, memory processes and other brain functions. Methodology/Principal Findings Here we show novel function phosphodiesterase inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, heterocyclic small molecule inhibitor 7,...
Cumulative evidence strongly supports that glycogen synthase kinase-3 (GSK-3) is a pathogenic molecule when it up-dysregulated, emerging as an important therapeutic target in severe unmet human diseases. GSK-3 specific inhibitors might be promising effective drugs for the treatment of devastating pathologies such neurodegenerative diseases, stroke, and mood disorders. As has ability to phosphorylate primed substrates, small molecules able bind this site should perfect drug candidates,...
Here, we describe a new family of melatonin–N,N-dibenzyl(N-methyl)amine hybrids that show balanced multifunctional profile covering neurogenic, antioxidant, cholinergic, and neuroprotective properties at low-micromolar concentrations. They promote maturation neural stem cells into neuronal phenotype thus they could contribute to CNS repair. also protect against mitochondrial oxidative stress, antioxidant properties, inhibit human acetylcholinesterase (AChE). Moreover, displace propidium from...
Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers potential severe CNS unmet diseases, being one the inhibitors on clinical trials different tauopathies. Following our hypothesis based enhanced reactivity residue Cys199 in binding site GSK-3, we examine here suitability phenylhalomethylketones as irreversible inhibitors. Our data confirm that halomethylketone unit essential inhibitory activity....
Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because current therapies only lead to temporary, limited improvement and have severe side effects, new approaches treat PD need be developed. To discover targets for potential therapeutic intervention, chemical genetic approach involving use small molecules as pharmacological tools has been implemented. First, screening an in-house library on...
Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors chronic treatments, we developed small molecules allowing subtle modulation activity. Design synthesis, structure-activity relationships, and binding mode quinoline-3-carbohydrazide derivatives as allosteric modulators are presented here. Furthermore, show how binders may overcome β-catenin side effects associated with strong inhibition. The therapeutic...
Glycogen synthase kinase (GSK-3beta) plays a crucial role in Alzheimer's disease (AD). Its inhibition is valid approach to the treatment of AD. In this initial letter, some thienyl and phenyl alpha-halomethyl ketones are described as new non-ATP competitive inhibitors GSK-3beta. They considered lead compounds for designing synthesizing series, carry out SAR studies, clear up mechanism action, and, general, evaluate their therapeutical usefulness.