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1.
Chem Biodivers ; 18(11): e2100361, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34547176

RESUMO

Rational modification of known drug candidates to design more potent ones using computational methods has found application in drug design, development, and discovery. Herein, we integrate computational and theoretical methodologies to unveil rivastigmine derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease (AD) management. The investigation entails pharmacokinetics screening, density functional theory (DFT) mechanistic study, molecular docking, and molecular dynamics (MD) simulation. We designed over 20 rivastigmine substituents, subject them to some analyses, and identified RL2 with an appreciable blood-brain barrier score and no permeability glycoprotein binding. The compound shows higher acylation energy and a favored binding affinity to the cholinesterase enzymes. RL2 interacts with the AChE and BuChE active sites showing values of -41.1/-39.5 kcal mol-1 while rivastigmine binds with -32.7/-30.7 kcal mol-1 for these enzymes. The study revealed RL2 (4-fluorophenyl rivastigmine) as a potential dual inhibitor for AChE and BuChE towards Alzheimer's disorder management.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Rivastigmina/farmacologia , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Teoria da Densidade Funcional , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Rivastigmina/síntese química , Rivastigmina/química
2.
Eur J Med Chem ; 184: 111745, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31585237

RESUMO

Hydrogen sulphide (H2S) is an endogenous gasotransmitter, largely known as a pleiotropic mediator endowed with antioxidant, anti-inflammatory, pro-autophagic, and neuroprotective properties. Moreover, a strong relationship between H2S and aging has been recently identified and consistently, a significant decline of H2S levels has been observed in patients affected by Alzheimer's disease (AD). On this basis, the use of H2S-donors could represent an exciting and intriguing strategy to be pursued for the treatment of neurodegenerative diseases (NDDs). In this work, we designed a small series of multitarget molecules combining the rivastigmine-scaffold, a well-established drug already approved for AD, with sulforaphane (SFN) and erucin (ERN), two natural products deriving from the enzymatic hydrolysis of glucosinolates contained in broccoli and rocket, respectively, endowed both with antioxidant and neuroprotective effects. Notably, all new synthetized hybrids exhibit a H2S-donor profile in vitro and elicit protective effects in a model of LPS-induced microglia inflammation. Moreover, a decrease in NO production has been observed in LPS-stimulated cells pre-treated with the compounds. Finally, the compounds showed neuroprotective and antioxidant activities in human neuronal cells. The most interesting compounds have been further investigated to elucidate the possible mechanism of action.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Sulfeto de Hidrogênio/farmacologia , Isotiocianatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Rivastigmina/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Sulfeto de Hidrogênio/síntese química , Sulfeto de Hidrogênio/química , Isotiocianatos/síntese química , Isotiocianatos/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Rivastigmina/síntese química , Rivastigmina/química , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/química , Sulfetos/farmacologia , Sulfóxidos , Tiocianatos/síntese química , Tiocianatos/química , Tiocianatos/farmacologia
3.
Mini Rev Med Chem ; 19(19): 1577-1598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31538893

RESUMO

Alzheimer, a progressive disease, is a common term for memory loss which interferes with daily life through severe influence on cognitive abilities. Based on the cholinergic hypothesis, and Xray crystallographic determination of the structure of acetylcholinesterase (AChE) enzyme, the level of acetylcholine (ACh, an important neurotransmitter associated with memory) in the hippocampus and cortex area of the brain has a direct effect on Alzheimer. This fact encourages scientists to design and synthesize a wide range of acetylcholinesterase inhibitors (AChEIs) to control the level of ACh in the brain, keeping in view the crystallographic structure of AChE enzyme and drugs approved by the Food and Drug Administration (FDA). AChEIs have slightly diverse pharmacological properties, but all of them work by inhibiting the segregation of ACh by blocking AChE. We reviewed significant scaffolds introduced as AChEIs. In some studies, the activity against butyrylcholinesterase (BuChE) has been evaluated as well because BuChE is a similar enzyme to neuronal acetylcholinesterase and is capable of hydrolyzing ACh. In order to study AChEIs effectively, we divided them structurally into 12 classes and briefly explained effective AChEIs and compared their activities against AChE enzyme.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Desenho de Fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Alcaloides/síntese química , Alcaloides/química , Doença de Alzheimer/patologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Donepezila/síntese química , Donepezila/química , Humanos , Rivastigmina/síntese química , Rivastigmina/química , Tacrina/síntese química , Tacrina/química
4.
Eur J Med Chem ; 181: 111572, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404859

RESUMO

The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Técnicas de Química Sintética , Desenho de Fármacos , Descoberta de Drogas , Animais , Técnicas de Química Sintética/métodos , Donepezila/análogos & derivados , Donepezila/síntese química , Donepezila/farmacologia , Dopaminérgicos/síntese química , Dopaminérgicos/química , Dopaminérgicos/farmacologia , Descoberta de Drogas/métodos , Humanos , Indanos/síntese química , Indanos/química , Indanos/farmacologia , Memantina/análogos & derivados , Memantina/síntese química , Memantina/farmacologia , Terapia de Alvo Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Nootrópicos/síntese química , Nootrópicos/química , Nootrópicos/farmacologia , Rivastigmina/análogos & derivados , Rivastigmina/síntese química , Rivastigmina/farmacologia , Tacrina/análogos & derivados , Tacrina/síntese química , Tacrina/farmacologia
5.
Eur J Med Chem ; 174: 216-225, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042617

RESUMO

The identification of a valid therapeutic treatment for Alzheimer's disease (AD) represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs) can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor) linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Fármacos Neuroprotetores/farmacologia , Rivastigmina/análogos & derivados , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Transformada , Quelantes/síntese química , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/toxicidade , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Rivastigmina/síntese química , Rivastigmina/toxicidade
6.
Molecules ; 23(9)2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30200331

RESUMO

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium⁻phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.


Assuntos
Rivastigmina/síntese química , Aminação , Avaliação Pré-Clínica de Medicamentos , Ligantes , Oxirredução , Rivastigmina/química
7.
Eur J Med Chem ; 141: 232-239, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031070

RESUMO

Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC50 values ranging from 340 to 378 nM. Analogously, all the compounds were able to inhibit the self ß-amyloid1-42 aggregation. The gallic acid hybrid GA2 as well as the 2-chromonecarboxylic acid hybrids CA1 and CA2 prevented the self-mediated Aß aggregation with percentages of inhibition ranging from 53% to 59%. Finally, some of them also show potent neuroprotective effects against glutamate-induced cell death and low toxicity in HT22 cells.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Produtos Biológicos/síntese química , Produtos Biológicos/química , Butirilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/metabolismo , Ácido Glutâmico/farmacologia , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Rivastigmina/síntese química , Rivastigmina/química , Relação Estrutura-Atividade
8.
ACS Chem Neurosci ; 8(11): 2522-2534, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28783948

RESUMO

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Pirazolonas/farmacologia , Pirimidinonas/farmacologia , Rivastigmina/farmacologia , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/química , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Estresse Oxidativo , Fragmentos de Peptídeos/química , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Agregação Patológica de Proteínas/prevenção & controle , Conformação Proteica , Pirazolonas/síntese química , Pirazolonas/química , Pirimidinonas/síntese química , Pirimidinonas/química , Rivastigmina/síntese química , Rivastigmina/química
9.
Bioorg Med Chem ; 25(1): 360-371, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27856236

RESUMO

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment.


Assuntos
Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Rivastigmina/análogos & derivados , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Humanos , Ligação de Hidrogênio , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Rivastigmina/síntese química , Rivastigmina/toxicidade , Relação Estrutura-Atividade
10.
Bioorg Chem ; 67: 105-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27317888

RESUMO

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer's disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via π-π interactions and (c) possible CH/π interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Rivastigmina/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Rivastigmina/síntese química , Rivastigmina/química , Estereoisomerismo , Relação Estrutura-Atividade
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