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1.
Artigo em Inglês | MEDLINE | ID: mdl-38598824

RESUMO

Amyloid-related diseases, such as Alzheimer's and Parkinson's disease, are devastating conditions caused by the accumulation of abnormal protein aggregates known as amyloid fibrils. While assays involving animal models are essential for understanding the pathogenesis and developing therapies, a wide array of standard analytical techniques exists to enhance our understanding of these disorders. These techniques provide valuable information on the formation and propagation of amyloid fibrils, as well as the pharmacokinetics and pharmacodynamics of candidate drugs. Despite ethical concerns surrounding animal use, animal models remain vital tools in the search for treatments. Regardless of the specific animal model chosen, the analytical methods used are usually standardized. Therefore, the main objective of this review is to categorize and outline the primary analytical methods used in in vivo assays for amyloid-related diseases, highlighting their critical role in furthering our understanding of these disorders and developing effective therapies.

2.
Cells ; 13(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474412

RESUMO

Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer's disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer's disease. This level of specificity could allow for more targeted and effective treatments. With ongoing research and development, it is hoped that these treatments can be refined and optimized to provide even greater benefits to patients. As our understanding of the underlying mechanisms of these diseases continues to grow, proximity-induced pharmacology treatments may become an increasingly important tool in the fight against dementia and other related conditions.


Assuntos
Doença de Alzheimer , Amiloidose , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo
4.
Eur J Med Chem ; 261: 115832, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37837674

RESUMO

Alzheimer's disease (AD) is a global health problem in the medical sector that will increase over time. The limited treatment of AD leads to the search for a new clinical candidate. Considering the multifactorial nature of AD, a strategy targeting number of regulatory proteins involved in the development of the disease is an effective approach. Here, we present a discovery of new multi-target-directed ligands (MTDLs), purposely designed as GABA transporter (GAT) inhibitors, that successfully provide the inhibitory activity against butyrylcholinesterase (BuChE), ß-secretase (BACE1), amyloid ß aggregation and calcium channel blockade activity. The selected GAT inhibitors, 19c and 22a - N-benzylamide derivatives of 4-aminobutyric acid, displayed the most prominent multifunctional profile. Compound 19c (mGAT1 IC50 = 10 µM, mGAT4 IC50 = 12 µM and BuChE IC50 = 559 nM) possessed the highest hBACE1 and Aß40 aggregation inhibitory activity (IC50 = 1.57 µM and 99 % at 10 µM, respectively). Additionally, it showed a decrease in both the elongation and nucleation constants of the amyloid aggregation process. In contrast compound 22a represented the highest activity and a mixed-type of eqBuChE inhibition (IC50 = 173 nM) with hBACE1 (IC50 = 9.42 µM), Aß aggregation (79 % at 10 µM) and mGATs (mGAT1 IC50 = 30 µM, mGAT4 IC50 = 25 µM) inhibitory activity. Performed molecular docking studies described the mode of interactions with GATs and enzymatic targets. In ADMET in vitro studies both compounds showed acceptable metabolic stability and low neurotoxicity. Successfully, compounds 19c and 22a at the dose of 30 mg/kg possessed statistically significant antiamnesic properties in a mouse model of amnesia caused by scopolamine and assessed in the novel object recognition (NOR) task or the passive avoidance (PA) task.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Camundongos , Animais , Butirilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Colinesterase/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Desenho de Fármacos , Ácido Aspártico Endopeptidases/metabolismo , Acetilcolinesterase/metabolismo
5.
Bioorg Med Chem ; 88-89: 117333, 2023 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-37236021

RESUMO

Butyrylcholinesterase (BuChE) and amyloid ß (Aß) aggregation remain important biological target and mechanism in the search for effective treatment of Alzheimer's disease. Simultaneous inhibition thereof by the application of multifunctional agents may lead to improvement in terms of symptoms and causes of the disease. Here, we present the rational design, synthesis, biological evaluation and molecular modelling studies of novel series of fluorene-based BuChE and Aß inhibitors with drug-like characteristics and advantageous Central Nervous System Multiparameter Optimization scores. Among 17 synthesized and tested compounds, we identified 22 as the most potent eqBuChE inhibitor with IC50 of 38 nM and 37.4% of Aß aggregation inhibition at 10 µM. Based on molecular modelling studies, including molecular dynamics, we determined the binding mode of the compounds within BuChE and explained the differences in the activity of the two enantiomers of compound 22. A novel series of fluorenyl compounds meeting the drug-likeness criteria seems to be a promising starting point for further development as anti-Alzheimer agents.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Acetilcolinesterase/metabolismo , Desenho de Fármacos , Estrutura Molecular , Simulação de Acoplamento Molecular
6.
Eur J Med Chem ; 250: 115169, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36753881

RESUMO

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid ß (Aß40) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aß40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aß40 aggregation with IC50 = 1.8 and 1.3 µM, respectively. Moreover, at 0.1-10 µM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aß aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Estrutura Molecular , Relação Estrutura-Atividade , Neuroblastoma/tratamento farmacológico , Desenho de Fármacos , Simulação de Acoplamento Molecular
7.
J Enzyme Inhib Med Chem ; 38(1): 2158822, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36629422

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a-3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman's method, Aß aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC50 = 0.131 µM; BuChE, IC50 = 0.116 µM; SI = 1.13), significant inhibition of Aß(1-42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Humanos , Doença de Alzheimer/tratamento farmacológico , Neuroproteção , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Estresse Oxidativo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
8.
Pharmaceutics ; 14(11)2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36365159

RESUMO

One of the pathological hallmarks of Alzheimer's disease (AD) is the formation of amyloid-ß plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid-ß aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aß40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aß40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.

9.
ACS Chem Neurosci ; 13(23): 3314-3329, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36445009

RESUMO

Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-ß (Aß) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aß clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aß and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aß42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood-brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 µM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aß42 expressing flies and generating a better outcome than doxycycline (50 µM). Moreover, 22 proved to be able to decrease Aß42 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual Aß/Tau aggregation inhibition in AD.


Assuntos
Doença de Alzheimer , Animais , Doença de Alzheimer/tratamento farmacológico , Drosophila , Proteínas tau , Drosophila melanogaster
10.
Methods Mol Biol ; 2538: 165-188, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35951300

RESUMO

Amyloid aggregation is linked to a number of human disorders that range from non-neurological illnesses such as type 2 diabetes to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The formation of insoluble protein aggregates with amyloid conformation inside bacteria, namely, in bacterial inclusion bodies, offers the possibility to use bacteria as simple models to study amyloid aggregation processes and potential effects of both anti-amyloid drugs and/or pro-aggregative compounds. This chapter describes fast, simple, inexpensive, highly reproducible, and tunable in vitro and in cellulo methods that use bacterial inclusion bodies as preliminary screening tools for anti-amyloid drugs.


Assuntos
Amiloidose , Diabetes Mellitus Tipo 2 , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Bactérias/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Corpos de Inclusão/metabolismo
11.
Pharmaceuticals (Basel) ; 15(6)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35745594

RESUMO

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aß42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.

12.
ACS Chem Neurosci ; 12(21): 4090-4112, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34652128

RESUMO

A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (Ki = 0.312 µM) and compound 22 on equine BChE (eqBChE) (Ki = 0.099 µM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV-vis spectroscopic studies showed that these compounds can form complexes with Cu2+ and Fe3+ and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Aß42 and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 µM on Aß42 and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cavalos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridinas , Pirimidinas/farmacologia , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 225: 113783, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34461507

RESUMO

Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid ß in vitro (75% for compound 17 and 68% for 35 at 10 µM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 µM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 µM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.


Assuntos
Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Indóis/farmacologia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Células Hep G2 , Cavalos , Humanos , Indóis/síntese química , Indóis/química , Ligantes , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Relação Estrutura-Atividade , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
14.
Eur J Med Chem ; 225: 113779, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34418785

RESUMO

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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Aminoquinolinas/síntese química , Aminoquinolinas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
15.
ACS Chem Neurosci ; 12(11): 2057-2068, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34019757

RESUMO

In Alzheimer's disease, neurons slowly degenerate due to the accumulation of misfolded amyloid ß and tau proteins. In our research, we performed extended studies directed at amyloid ß and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer's agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18, which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aß42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 µM), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and Aß (hBuChE IC50 = 5.74 µM; hBACE1 IC50 = 41.6 µM; Aß aggregation (aggr.) inh. IC50 = 3.09 µM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aß vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Simulação por Computador , Desenho de Fármacos , Humanos , Cinética , Fragmentos de Peptídeos , Relação Estrutura-Atividade
16.
Chemistry ; 27(19): 6015-6027, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33666306

RESUMO

Many (poly-)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid-ß 42 (Aß42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aß42, which adopts different folds, affecting the propensity to populate fibril-like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aß42 aggregation inhibition, glutamate-induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV-2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 µm (83 % cell survival), whereas curcumin only showed very low protection at 10 µm (21 % cell survival).


Assuntos
Amiloidose , Curcumina , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Curcumina/farmacologia , Humanos , Estresse Oxidativo
17.
Biomacromolecules ; 22(2): 430-440, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33416315

RESUMO

Alzheimer's disease (AD), affecting almost 50 million individuals worldwide, is currently the first cause of dementia. Despite the tremendous research efforts in the last decade, only four supportive or palliative drugs, namely, acetylcholinesterase (AChE) inhibitors donepezil, galantamine, and rivastigmine and the glutamate NMDA receptor antagonist memantine, are currently available. New therapeutic strategies are becoming prominent, such as the direct inhibition of amyloid formation or the regulation of metal homeostasis. In the present report, the potential use of Prussian blue (PB), a drug that is in the World Health Organization Model List of Essential Medicines, in AD treatment is demonstrated. Both in vitro and in cellulo studies indeed suggest that PB nanoparticles (PBNPs) are capable of reducing the formation of typical amyloid-ß fibers (detected by thioflavin T fluorescence) and restoring the usual amyloid fibrillation pathway via chelation/sequestration of copper, which is found in high concentrations in senile plaques.


Assuntos
Doença de Alzheimer , Nanopartículas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Cobre , Ferrocianetos , Humanos , Conformação Proteica em Folha beta
18.
Molecules ; 25(23)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33297547

RESUMO

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aß) aggregation, a hallmark of pathophysiology of Alzheimer's disease. The newly synthesized molecules spanned their IC50 values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the 'active' compounds from the 'inactive' (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of 'active' compounds, i.e., those achieving finite IC50 values lower than 100 µM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q2 = 0.596) and in the external test set (n = 14, r2ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aß anti-aggregating potency of the indole and isatin derivatives studied herein.


Assuntos
Peptídeos beta-Amiloides/química , Indóis/química , Isatina/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Técnicas de Química Sintética , Citoproteção/efeitos dos fármacos , Desenho de Fármacos , Humanos , Indóis/farmacologia , Isatina/farmacologia , Ligantes , Conformação Molecular , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos
19.
J Enzyme Inhib Med Chem ; 35(1): 1944-1952, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33092411

RESUMO

Effective therapy of Alzheimer's disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands - 5-HT6 receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their ß-secretase, tau, and amyloid ß aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid ß aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC50=4 µM, h5TH6 K i=94 nM, hAChE IC50=26 nM, and eqBuChE IC50=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Receptores de Serotonina/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/prevenção & controle , Inibidores da Colinesterase/metabolismo , Desenho de Fármacos , Escherichia coli , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligantes , Modelos Moleculares , Agregados Proteicos , Relação Estrutura-Atividade
20.
J Med Chem ; 63(17): 9360-9390, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32706255

RESUMO

Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, ß-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Aß42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/química , Antioxidantes/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Terapia de Alvo Molecular , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Benzopiranos/metabolismo , Benzopiranos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Camundongos , Simulação de Dinâmica Molecular , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade , Conformação Proteica
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