A5064150038- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Synthesis of Organic Compounds
- Estrogen and related hormone effects
- Synthesis and biological activity
- Alzheimer's disease research and treatments
- Bioactive Compounds and Antitumor Agents
- Chemical synthesis and alkaloids
- Biological Activity of Diterpenoids and Biflavonoids
- Curcumin's Biomedical Applications
- Multicomponent Synthesis of Heterocycles
- Cancer therapeutics and mechanisms
- Nicotinic Acetylcholine Receptors Study
- Bioactive natural compounds
- Synthesis of heterocyclic compounds
- Pharmacological Receptor Mechanisms and Effects
- Synthesis and Biological Evaluation
- Cannabis and Cannabinoid Research
- Chemical Synthesis and Analysis
- Asymmetric Synthesis and Catalysis
- Click Chemistry and Applications
- Natural product bioactivities and synthesis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis of Indole Derivatives
- Eicosanoids and Hypertension Pharmacology
University of Bologna
2015-2024
University of Siena
2009
Universität Innsbruck
2009
Saarland University
2001-2008
Université de Bordeaux
2008
Max Planck Institute for Informatics
2008
University of Szeged
2006
University of Basilicata
2005
University of Padua
2002-2003
University College London
2001
In recent years, the investigation of acetylcholinesterase (AChE) inhibitors has gained further interest, because involvement peripheral site enzyme in β-amyloid (Aβ) aggregation process been disclosed. We present here, for first time, a direct evidence Aβ antiaggregating action an AChE inhibitor (AP2238) purposely designed to bind at both catalytic and sites human enzyme.
The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multitarget strategies combat causes and symptoms. We therefore designed, synthesized, tested new hybrid molecules linking a benzofuran ring N-methyl-N-benzylamine through heptyloxy chain, affording series potential multifunctional drugs for AD. cholinesterase inhibitory activity was extended the inhibition Aβ fibril formation 1, 3, 5. Compound 3 showed an additional neuroprotective effect.
The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such Alzheimer's disease (AD). concurrent inhibition of the validated AD targets β-secretase (BACE-1) glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid tau protein cascades been identified promising therapeutic strategy. In our study, curcumin was lead compound for simultaneous targets; therefore, synthetic efforts were dedicated obtaining small library...
In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related tacrine, drug currently in use treatment Alzheimer's disease. To aim, synthesized and tested series 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted positions 6 7 acridine nucleus bearing selected groups on 9-amino function. By means Hansch approach, QSAR equations were obtained, quantitatively accounting both detrimental steric effect substituents...
The modulation of the endocannabinoid system is emerging as a viable avenue for treatment neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing signaling to therapeutic levels through FAAH inhibition might be beneficial neurodegenerative disorders such Alzheimer's disease, effectively preventing or slowing progression disease. Hence, search more effective this paper, multitarget-directed ligand paradigm was applied design...
Somatic mutations of the Estrogen Receptor α (ERα) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated acquired resistance, disease relapse, and increased mortality rates, hence representing a current major clinical challenge. Here, multi-microseconds (12.5 µs) molecular dynamics simulations revealed that recurrent ERα (i. e. L536Q, Y537S, Y537N, D538G) (mERα) constitutively active their...
Aromatase (P450arom) is a target of pharmacological interest for the treatment breast cancer. In this paper, we report design, synthesis, and in vitro biological evaluation series new (di)benzopyranone-based inhibitors enzyme. The design compounds was guided by CoMFA model previously developed nonsteroidal aromatase inhibitors. Both chromone xanthone nuclei were taken as molecular skeletons, functions supposed to be critical binding active site − heterocyclic ring (imidazole or...
Following our SAR studies on aromatase inhibitors, new compounds were designed by appropriately modifying the structure of flavone 1 using previously reported CoMFA model. While introduction substituents 2-phenyl ring alone did not cause improvement in potency, these modifications and removal 7-methoxy group led to showing inhibitory activity nanomolar range, comparable marketed drug fadrozole.
In continuing research that led us to identify a new class of carbamate derivatives acting as potent (Rampa et al. J. Med. Chem. 1998, 41, 3976) and long-lasting 2001, 44, 3810) acetylcholinesterase (AChE) inhibitors, we obtained some analogues able simultaneously block both the catalytic β-amyloid (Aβ) proaggregatory activities AChE. The key feature these is 2-arylidenebenzocycloalkanone moiety provides ability bind at AChE peripheral site responsible for promoting Aβ aggregation....
AP2238 was the first compound published to bind both anionic sites of human acetylcholinesterase, allowing simultaneous inhibition catalytic and amyloid-β pro-aggregating activities AChE. Here we attempted derive a comprehensive structure−activity relationship picture for this molecule, affording 28 derivatives which AChE BChE inhibitory were evaluated. Selected compounds also tested their ability prevent AChE-induced Aβ-aggregation. Moreover, docking simulations molecular orbital...
Pharmacophore modeling of a series aldosterone synthase (CYP11B2) inhibitors triggered the design compounds 11 and 12 by extending previously established naphthalene molecular scaffold (e.g., present in molecules 1 2) via introduction phenyl or benzyl residue 3-position. These additional aromatic moieties have been hypothesized to fit into newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies our refined CYP11B2 protein model performed prior synthesis estimate...
Suppression of tumor and plasma estrogen levels by inhibition aromatase is one the most effective treatments for postmenopausal breast cancer patients. Starting from an easy, synthetically accessible, benzophenone scaffold, a new class potent inhibitors was synthesized, endowed with high selectivity respect to 17α-hydroxylase/17,20-lyase (CYP17). Compounds 1b 1d proved be among described so far.
In further pursuing our search for potent and selective aromatase inhibitors, a new series of molecules was designed synthesized, exploring possible structural modifications previously identified xanthone scaffold. Among them, highly compounds, with inhibitory activity in the low nanomolar range, were found. particular, substitution heterocyclic oxygen atom core by sulfur and/or increase structure flexibility seemed to be favorable interaction enzyme.
Common copathogenic factors, including oxidative stress and neuroinflammation, are found to play a vital role in the development of neurodegenerative disorders, Alzheimer's disease (AD) Parkinson's (PD). Nowadays, owing multifactorial character diseases, no effective therapies available, thus underlying need for new strategies. Overexpression enzyme GSK-3β downregulation Nrf2/ARE pathway responsible decrease antioxidant defense effects. These pieces evidence underline usefulness dual...
Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes compounds in search for an effective treatment Alzheimer's disease. This work describes synthesis, AChE inhibitory activity, and structure−activity relationships some related to a recently discovered series inhibitors: ω-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones. The influence structural variations on potency was carefully by modifying different parts parent molecule,...
To identify enantioselective nonsteroidal aromatase inhibitors, a multidisciplinary medicinal chemistry approach was pursued. First, our earlier CoMFA model [Bioorg. Med. Chem. 1998, 6, 377−388] extended taking purposely into account previously discovered inhibitors. The 3D QSAR then exploited to design chiral ligands, whose configurational assignment obtained, after HPLC separation, by means of combination circular dichroism measurements and time dependent density functional calculations....