A5090475908- Cholinesterase and Neurodegenerative Diseases
- Histone Deacetylase Inhibitors Research
- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- European and International Law Studies
- Neuroscience and Neuropharmacology Research
- Computational Drug Discovery Methods
- EU Law and Policy Analysis
- Neurogenesis and neuroplasticity mechanisms
- European Criminal Justice and Data Protection
- Taxation and Legal Issues
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Nuclear Receptors and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Nitric Oxide and Endothelin Effects
- European and International Contract Law
- Metabolism and Genetic Disorders
- Amino Acid Enzymes and Metabolism
- Nerve injury and regeneration
- Neurological Disease Mechanisms and Treatments
- Corporate Governance and Law
- Intellectual Property Law
- Adenosine and Purinergic Signaling
- Medicinal Plants and Neuroprotection
University of Bologna
2016-2025
Azienda Ospedaliera San Gerardo
2023
University of Milano-Bicocca
2023
Universidade do Vale do Itajaí
2022
Covington and Burling
2018-2021
Ospedale Koelliker
2002-2004
Brown University
2001
Don Carlo Gnocchi Foundation
2000
The role so far ascribed to intracellular CuZn superoxide dismutase is that of an scavenger oxygen radicals. However, other functions cytosolic have been hypothesized. For example, incubated with rat hepatocyte cells in culture inhibits 3-hydroxy-3methylglutaryl CoA reductase, thereby reducing cholesterol synthesis. We recently demonstrated the presence surface membrane receptors for dismutase, suggesting possible autocrine or paracrine activities. aim present study was investigate whether...
We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and tacrine fragment. In vitro, 15 displayed excellent acetylcholinesterase (AChE) inhibitory potencies interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis one those in complex with AChE allowed rationalizing outstanding activity data (IC50 = 0.72 nM). Two showed negligible toxicity immortalized mouse cortical neurons Neuro2A primary rat cerebellar...
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, development of multitarget drugs which involved both pathways might represent a promising therapeutic strategy. Accordingly, reported here is discovery 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as first class molecules able simultaneously modulate BACE-1 GSK-3β. Notably, one triazinone showed...
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 cAMP response element-binding protein (CREB) is an evolutionarily conserved transcription regulator essential for long-term memory formation. It not known, however, whether the molecular events downstream of CREB activation are also conserved. An early, cAMP-dependent event necessary learning-related synaptic plasticity in invertebrate Aplysia californica induction factor CCAAT enhancer-binding (C/EBP). Here we show that two homologs rat, C/EBPbeta and C/EBPdelta, induced at discrete...
Abstract Herein we describe the design, multicomponent synthesis, and biological, molecular modeling ADMET studies, as well in vitro PAMPA‐blood–brain barrier (BBB) analysis of new tacrine–ferulic acid hybrids (TFAHs). We identified ( E )‐3‐(hydroxy‐3‐methoxyphenyl)‐ N ‐{8[(7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐yl)amino]octyl}‐ ‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n ) a particularly interesting multipotent compound that shows moderate completely selective inhibition human...
One of the main obstacles toward discovery effective anti-Alzheimer drugs is multifactorial nature its etiopathology. Therefore, use multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, well cognitive neurogenic functions, are fostered come. In this respect, we report herein on first class BACE-1/GSK-3β dual inhibitors based a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton,...
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed for neurodegenerative diseases incorporate antioxidant effects without losing affinity selectivity at HDAC6. Structure-activity relationships led compound 10b as a hybrid molecule showing pronounced selective inhibition HDAC6 (IC50 = 30.7 nM, > 25-fold over other subtypes). This shows comparable DPPH radical scavenging ability acid, ORAC...
A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, enzyme kinetics, antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, assays applied to investigate effects using murine hippocampal HT22 cells immunomodulatory on the microglial N9 cell line. MTDLs retained antioxidative compared...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications promote its aggregation the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates cellular animal models; thus, TTBK1 inhibitors emerge as promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase–ligand complex structure determination,...
Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on reported connection among histone deacetylases (HDACs) glycogen synthase kinase 3β (GSK-3β), herein we present discovery biochemical characterization first-in-class hit compound able to exert promising anti-AD effects by modulating targeted proteins low micromolar range concentration. Compound 11 induces an increase...
We have designed and synthesized a series of 14 hybrid molecules out the cholinesterase (ChE) inhibitor tacrine benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist investigated them in vitro vivo. The compounds are potent ChE inhibitors, for most promising hybrids, mechanism acetylcholinesterase (hAChE) inhibition as well their ability to interfere with AChE-induced aggregation β-amyloid (Aβ), Aβ self-aggregation was assessed. All hybrids were evaluated affinity...
We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB2R) ligands for treatment neurodegeneration. In total, 15 benzimidazole carbamates were synthesized tested their inhibition cholinesterases, also with regard to pseudoirreversible binding mode affinity toward both cannabinoid receptors in radioligand studies. After evaluation a calcium mobilization assay as well β-arrestin (βarr2) recruitment assay, two compounds...
Abstract Elimination of neurons produced in excess naturally occurs during brain development through programmed cell death. Among the many survival factors affecting this process, a role for neurotransmitters acting on specific receptors has been suggested. We have performed an vivo pharmacological blockade N‐methyl‐ d ‐aspartate (NMDA) subtype glutamate receptors, using competitive NMDA receptor antagonist CGP 39551 at developmental stages corresponding to those which dependence stimulation...