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1.
Chem Biol Interact ; 326: 109139, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32454005

RESUMO

Since several decades oximes have been used as part of treatment of nerve agent intoxication with the aim to restore the biological function of the enzyme acetylcholinesterase after its covalent inhibition by organophosphorus compounds such as pesticides and nerve agents. Recent findings have illustrated that, besides oximes, certain Mannich phenols can reactivate the inhibited enzyme very effectively, and may therefore represent an attractive complementary class of reactivators. In this paper we further probe the effect of structural variation on the in vitro efficacy of Mannich phenol based reactivators. Thus, we present the synthesis of 14 compounds that are close variants of the previously reported 4-amino-2-(1-pyrrolidinylmethyl)-phenol, a very effective non-oxime reactivator, and 3 dimeric Mannich phenols. All compounds were assessed for their ability to reactivate human acetylcholinesterase inhibited by the nerve agents VX, tabun, sarin, cyclosarin and paraoxon in vitro. It was confirmed that the potency of the compounds is highly sensitive to small structural changes, leading to diminished reactivation potency in many cases. However, the presence of 4-substituted alkylamine substituents (as exemplified with the 4-benzylamine-variant) was tolerated. More surprisingly, the dimeric compounds demonstrated non-typical behavior and displayed some reactivation potency as well. Both findings may open up new avenues for designing more effective non-oxime reactivators.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/química , Agentes Neurotóxicos/farmacologia , Oximas/química , Oximas/farmacologia , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/farmacologia , Reativadores da Colinesterase/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Relação Estrutura-Atividade
2.
Food Chem ; 327: 127045, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32464460

RESUMO

In this study, the inhibitory potentials of food originated 34 phenolic acids, and flavonoid compounds were screened against acetylcholinesterase, butyrylcholinesterase, urease, and tyrosinase enzymes. All compounds included in this study exhibited high antioxidant activity with an ignorable cytotoxic activity. In general, they also showed poor anti-urease and anti-tyrosinase activities. Compounds in aglycone form (quercetin, myricetin, chrysin, and luteolin) showed strong anticholinesterase activities. No relation was observed between the tested bioactivities except from the case that aglycone compounds exhibited a strong positive relationship between antioxidant activities and anticholinesterase activity. Interestingly, there was a relation between the molecular weights of aglycone compounds and their anticholinesterase activities. The study showed that flavonoids with molecular mass of 250-320 g/mol have high potential of anticholinesterase activities and are valuable for future experiments on animals and humans. Potential inhibitory effects of these molecules on target proteins were investigated using docking and molecular dynamics calculations.


Assuntos
Inibidores da Colinesterase/química , Flavonoides/química , Hidroxibenzoatos/química , Plantas Comestíveis/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/química , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Flavonoides/metabolismo , Flavonoides/farmacologia , Humanos , Hidroxibenzoatos/metabolismo , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Plantas Comestíveis/metabolismo
3.
Eur J Med Chem ; 200: 112415, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454229

RESUMO

As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC50 values of ≤0.72 µM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the π-π action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents.


Assuntos
Benzofenantridinas/química , Inibidores da Colinesterase/química , Descoberta de Drogas , Sítios de Ligação , Butirilcolinesterase , Inibidores da Colinesterase/metabolismo , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Isoquinolinas/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 68(10): 3140-3148, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053361

RESUMO

3-O-Cinnamoylepicatechin (1) was synthesized along with four flavoalkaloids, (-)-6-(5‴S)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (2), (-)-6-(5‴R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (3), (-)-8-(5‴S)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (4), and (-)-8-(5‴R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (5) via esterification of epicatechin followed by phenolic Mannich reaction of 1 with theanine in the presence of heat. The new compounds 1-5 were detected in leaves of three tea cultivars, Fuding-Dabai, Huangjingui, and Zimudan with the help of ultra-performance liquid chromatography hyphenated with a photodiode array detector and electrospray ionization high-resolution mass spectrometry (UPLC-PDA-ESI-HRMS), suggesting that they are naturally occurring in tea leaves. The structures of the novel natural products were characterized by one- and two-dimensional nuclear magnetic resonance (1D and 2D NMR) and mass spectroscopy. Compounds 1-5 were then evaluated for their acetylcholinesterase (AChE) inhibitory effect (IC50 = 0.12-1.02 µM). The availability of the synthesized epicatechin derivatives 1-5 via a synthetic route enabled the first unequivocal identification of these derivatives as tea secondary metabolites and made it possible to determine their content in the tea material as well as the diverse bioactivities.


Assuntos
Alcaloides/química , Camellia sinensis/química , Inibidores da Colinesterase/química , Extratos Vegetais/química , Acetilcolinesterase/química , Cromatografia Líquida de Alta Pressão , Folhas de Planta/química , Espectrometria de Massas por Ionização por Electrospray
5.
J Chromatogr A ; 1618: 460942, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32057448

RESUMO

The fruit of Schisandra chinensis (Chinese magnolia vine), the medicinal plant well-known in Traditional Chinese Medicine, gains great popularity in the modern phytopharmacology. This phenomena is related to the wide and powerful healing properties, including supporting immune, nervous and digestive systems activity. S. chinensis is also known for its adaptogenic properties which can support the treatment of neurodegenerative disorders, particularly Alzheimer's disease. The components of S. chinensis have been analyzed mostly using chromatography, including HPLC, GC and TLC. The last technique can be easily hyphenated with biological assays performed directly on a TLC plate that is using effect directed detection. TLC-direct bioautography (TLC-DB) for acetylcholinesterase (AChE) inhibition and TLC-DB against Bacillus subtilis were performed, followed by micro-preparative separation of fractions which were subsequently subjected to LC-MS tentative identification. Additionally, screening analysis was done using both biological detection and derivatization reagents (e.g. PMA, thymol, NP-PEG). Both TLC screening and effect-directed analysis (TLC-DB followed by MS analysis) of S. chinensis fruit revealed components with biological activity, especially antibacterials (e.g. citric acid) and inhibitors of AChE (mainly dibenzocyclooctadiene lignans). AChE inhibition activities were confirmed by TLC-DB for nine standards that is: 6-O-benzoylgomisin, deoxyschisandrin, gomisin A, gomisin G, schisandrin, schisandrin C, schisanhenol, schisantherin A and schisantherin B. These lignans were further identified by LC-ESI-MS in the isolated fraction revealing AChE inhibition. Moreover three other lignans: γ-schisandrin, schisandrin B and gomisin J were tentatively identified by LC-ESI-MS.


Assuntos
Cromatografia em Camada Delgada/métodos , Lignanas/análise , Schisandra/química , Acetilcolinesterase , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Cromatografia Líquida , Ciclo-Octanos/análise , Frutas/química , Lignanas/química , Espectrometria de Massas
6.
J Enzyme Inhib Med Chem ; 35(1): 498-505, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914836

RESUMO

Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.


Assuntos
Amidas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Corantes Fluorescentes/farmacologia , Amidas/síntese química , Amidas/química , Animais , Butirilcolinesterase/isolamento & purificação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular
7.
J Enzyme Inhib Med Chem ; 35(1): 460-467, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899981

RESUMO

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.HIGHLIGHTSSeries of oxazole benzylamines were designed and synthesisedThe tested compounds showed binding selectivity for BChENaphthoxazoles were more potent AChE inhibitors.


Assuntos
Benzilaminas/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Oxazóis/química , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Técnicas Eletroquímicas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Processos Fotoquímicos , Relação Estrutura-Atividade
8.
Chem Commun (Camb) ; 56(16): 2459-2462, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31996889

RESUMO

A thermoresponsive NIPAAm-based polymer is combined with the selective acetylcholinesterase inhibitor tacrine in order to create a strict in sense on/off switch for enzymatic activity. This polymer-inhibitor conjugate inhibits AChE at room temperature and enables reactivation of AChE by heating above the cloud point of the conjugate.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Polímeros/farmacologia , Tacrina/farmacologia , Temperatura , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Estrutura Molecular , Polímeros/síntese química , Polímeros/química , Tacrina/síntese química , Tacrina/química
9.
Food Chem ; 314: 126181, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954938

RESUMO

The study analyzed the inhibitory effects (IC50) of crude and purified extracts from Maliniak, Cerise, Black Prince and Lima tomatoes on the formation of advanced glycation end products (AGEs), the activity of angiotensin-converting (ACE) and acetylcholinesterase (AChE) enzymes. Polyphenol composition (LC-MS) and antioxidant capacity (PCL, FRAP) were measured. The purified extracts of Black Prince tomatoes were the most potent inhibitors of AGEs in BSA-GLU (7.20mg/mL) and BSA-MGO (9.53mg/mL) models. The purified extracts of Cerise and Black Prince tomatoes had the highest ACE (0.50-0.44mg/mL) and AChE (7.93-5.83mg/mL) inhibitory activity. Cerise variety showed the highest polyphenol concentrations in crude (488.93µg/g DM) and purified (8394.99µg/g DM) extracts. The highest PCLACW and FRAP values were found for Cerise purified extracts (71.83 and 87.78µmol Trolox/g DM). Caffeic acid, caffeoyl-glucose, linocaffein, glucosyl-coumarate, vanillic acid, rutin and TPI values were significantly correlated with BSA-MGO, anti-ACE, anti-AChE and PCLACW parameters.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Colinesterase/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Lycopersicon esculentum/química , Extratos Vegetais/farmacologia , Polifenóis/análise , Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/análise , Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Extratos Vegetais/isolamento & purificação , Especificidade da Espécie
10.
Pharm Res ; 37(3): 34, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942651

RESUMO

PURPOSE: Alzheimer's disease is a neurodegenerative disorder, and most common form of dementia afflicting over 35 million people worldwide. Rivastigmine is a widely used therapeutic for ameliorating clinical manifestations of Alzheimer's disease. However, current treatments require frequent dosing either orally or via transdermal patch that lead to compliance issues and administration errors risking serious adverse effects. Our objective was to develop a smart polymer based delivery system for controlled release of rivastigmine over an extended period following a single subcutaneous injection. METHODS: Rivastigmine release was optimized by tailoring critical factors including polymer concentration, polymer composition, drug concentration, solvent composition, and drug hydrophobicity (rivastigmine tartrate vs base). Optimized in vitro formulation was evaluated in vivo for safety and efficacy. RESULTS: Formulation prepared using PLGA (50:50) at 5% w/v in 95:5 benzyl benzoate: benzoic acid demonstrated desirable controlled drug release characteristics in vitro. The formulation demonstrated sustained release of rivastigmine tartrate for 7 days in vivo with promising biocompatibility and acetylcholinesterase inhibition efficacy for 14 days. CONCLUSION: The results exemplify an easily injectable controlled release formulation of rivastigmine prepared using phase-sensitive smart polymer. The optimized formulation significantly increases the dosing interval, and can potentially improve patient compliance as well as quality of life of patients living with Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Rivastigmina/química , Polímeros Responsivos a Estímulos/química , Inibidores da Colinesterase/administração & dosagem , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Transição de Fase , Rivastigmina/administração & dosagem , Solventes/química
11.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936622

RESUMO

Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar ß-amyloid 1-42 (Aß42), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA's) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds 7 and 11 with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Ácidos Cumáricos/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , Acetilcolina/metabolismo , Acetilcolinesterase , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/química , Ácido Glutâmico/genética , Humanos , Ferro/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia
12.
Chem Biodivers ; 17(1): e1900600, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31793197

RESUMO

Four new hetisine-type C20 -diterpenoid alkaloids, named as coreanines A-D (1-4), were isolated from the roots of Aconitum coreanum, together with thirteen known alkaloids (5-17). Their structures were elucidated by extensive spectroscopic methods including IR, HR-ESI-MS and NMR techniques. All the isolated compounds were screened for the acetylcholinesterase (AChE) inhibitory effects, and none of them showed considerable inhibitory activity.


Assuntos
Acetilcolinesterase/metabolismo , Aconitum/química , Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Diterpenos/farmacologia , Raízes de Plantas/química , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Electrophorus , Estrutura Molecular
13.
Eur J Med Chem ; 187: 111916, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812794

RESUMO

Complex pathomechanism of Alzheimer's disease (AD) prompts researchers to develop multifunctional molecules in order to find effective therapy against AD. We designed and synthesized novel multifunctional ligands for which we assessed their activities towards butyrylcholinesterase, beta secretase, amyloid beta (Aß) and tau protein aggregation as well as antioxidant and metal-chelating properties. All compounds showed dual anti-aggregating properties towards Aß and tau protein in the in cellulo assay in Escherichia coli. Of particular interest are compounds 24b and 25b, which efficiently inhibit aggregation of Aß and tau protein at 10 µM (24b: 45% for Aß, 53% for tau; 25b: 49% for Aß, 54% for tau). They display free radical scavenging capacity and antioxidant activity in ABTS and FRAP assays, respectively, and selectively chelate copper ions. Compounds 24b and 25b are also the most potent inhibitors of BuChE with IC50 of 2.39 µM and 1.94 µM, respectively. Promising in vitro activities of the presented multifunctional ligands as well as their original scaffold are a very interesting starting point for further research towards effective anti-AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Butirilcolinesterase/metabolismo , Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Pirrolidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Quelantes/síntese química , Quelantes/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Recuperação de Fluorescência Após Fotodegradação , Cavalos , Humanos , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores
14.
Chem Pharm Bull (Tokyo) ; 68(2): 161-166, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813907

RESUMO

Discovery of novel multifunctional inhibitors targeting acetylcholinesterase (AChE) has becoming a hot spot in anti-Alzheimer's disease (AD) drug development. In the present study, four potent small molecule inhibitors (A01, A02, A03 and A04) of AChE with new chemical scaffold were identified. Inhibitor A03 displayed the most potent inhibition activity on AChE at enzymatic level with IC50 value of 180 nM, and high selectivity towards AChE over butyrylcholinesterase (BChE) by more than 100-fold. The binding modes of compounds A01-A04 were carefully analyzed by molecular docking and molecular dynamics (MD) simulation to provide informative clues for further structure modification. Finally, the anti-amyloid beta (Aß) aggregation and neuroprotective activity were also well investigated. Our findings highlighted the therapeutic promise of AChE inhibitors A01-A04 for AD treatment.


Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Desenho de Fármacos , Descoberta de Drogas , Cavalos , Humanos , Simulação de Acoplamento Molecular , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/prevenção & controle
15.
Nat Prod Res ; 34(4): 549-552, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30445826

RESUMO

The aim of this study was to determine, for the first time, the chemical composition of Peltigera horizontalis thallus and apothecia extracts (ether, ethyl acetate, dichloromethane and acetone) by HPLC-UV and GC-MS, and evaluate activity of genotoxic, anticholinesterase, antioxidant and antibacterial potential of acetone extracts. Major constituents of thallus extracts were gyrophoric acid, and methyl gyrophorate while dominant component of apothecia extracts was tenuiorin. The predominant volatile compounds in extracts were methyl orsellinate, dodecyl acrylate, orcinol and orcinol monomethyl ether. The thallus acetone extract at concentration of 2.0 µg mL-1 gave the greatest decrease in the micronuclei frequency (22.4%) of all tested extracts. Apothecia extract showed stronger antioxidant activity as compared to thallus extract. Tested extracts at concentration of 10 mg mL-1 exhibited inhibitory effect (16.5% for thallus and 12.8% for apothecia) on pooled human serum cholinesterase. P. horizontalis acetone extracts had no activity against the tested five bacteria strains.


Assuntos
Antibacterianos/isolamento & purificação , Antioxidantes/isolamento & purificação , Ascomicetos/química , Inibidores da Colinesterase/isolamento & purificação , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Extratos Vegetais/química , Resorcinóis/análise
16.
Nat Prod Res ; 34(3): 425-428, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30450961

RESUMO

Phytochemical investigation of Illicium micranthum led to the isolation of two new prenylated C6-C3 compounds, 12-O-methyl-2,3-dehydroillifunone C (1) and illiciminone A (2), together with three known analogues (3-5) and one known sesquiterpene lactone (6). The structures were established by extensive spectroscopic characterization and the reported data. All the isolates were evaluated for their acetylcholinesterase (AChE) inhibition activity. Compound 5 showed weak inhibitory activity (46.0%) at 50 µM concentration.


Assuntos
Illicium/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Lactonas/química , Lactonas/isolamento & purificação , Estrutura Molecular , Prenilação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Análise Espectral
17.
J Enzyme Inhib Med Chem ; 35(1): 118-128, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694418

RESUMO

A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 µM for eeAChE; IC50 = 0.16 µM for hAChE), and it was also the best inhibitor to AChE-induced Aß aggregation (29.02% at 100 µM) and an efficient inhibitor to self-induced Aß aggregation (30.67% at 25 µM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Quinolonas/química , Tiocarbamatos/química , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Desenho de Fármacos , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos
18.
J Enzyme Inhib Med Chem ; 35(1): 211-226, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31760822

RESUMO

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aß aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aß1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Benzofuranos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Tacrina/química
19.
J Enzyme Inhib Med Chem ; 35(1): 31-41, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31645149

RESUMO

The present study describes the synthesis of a novel series of thiazolidin-4-one and thiazinan-4-one using 1-(2-aminoethyl)pyrrolidine as amine precursor. All compounds were synthesised by one-pot three component cyclocondensation reaction from the amine, a substituted benzaldehyde and a mercaptocarboxylic acid. The compounds were obtained in moderate to good yields and were identified and characterised by 1H, 13 C, 2 D NMR and GC/MS techniques. The compounds also were screened for their in vitro acetylcholinesterase (AChE) activity in hippocampus and cerebral cortex on Wistar rats. The six most potent compounds have been investigated for their cytotoxicity by cell viability assay of astrocyte primary culture, an important cell of central nervous system. We highlighted two compounds (6a and 6k) that had the lowest IC50 in hippocampus (5.20 and 4.46 µM) and cerebral cortex (7.40 and 6.83 µM). These preliminary and important results could be considered a starting point for the development of new AChE inhibitory agents.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Tiazinas/farmacologia , Tiazolidinas/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química , Tiazolidinas/síntese química , Tiazolidinas/química
20.
J Enzyme Inhib Med Chem ; 35(1): 330-343, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31856607

RESUMO

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzimidazóis/síntese química , Benzimidazóis/química , Butirilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Células Hep G2 , Cavalos , Humanos , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
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