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1.
Rev Bras Parasitol Vet ; 30(2): e002221, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076049

RESUMO

This study reports the action of essential oils (EO) from five plants on the activity of native and recombinant acetylcholinesterases (AChE) from Rhipicephalus microplus. Enzyme activity of native susceptible AChE extract (S.AChE), native resistant AChE extract (R.AChE), and recombinant enzyme (rBmAChE1) was determined. An acetylcholinesterase inhibition test was used to verify the effect of the EO on enzyme activity. EO from Eucalyptus globulus, Citrus aurantifolia, Citrus aurantium var.dulcis inhibited the activity of S.AChE and R.AChE. Oils from the two Citrus species inhibited S.AChE and R.AChE in a similar way while showing greater inhibition on R.AChE. The oil from E. globulus inhibited native AChE, but no difference was observed between the S.AChE and R.AChE; however, 71% inhibition for the rBmAChE1 was recorded. Mentha piperita oil also inhibited S.AChE and R.AChE, but there was significant inhibition at the highest concentration tested. Cymbopogon winterianus oil did not inhibit AChE. Further studies are warranted with the oils from the two Citrus species that inhibited R.AChE because of the problem with R. microplus resistant to organophosphates, which target AChE. C. winterianus oil can be used against R. microplus populations that are resistant to organophosphates because its acaricidal properties act by mechanism(s) other than AChE inhibition.


Assuntos
Acaricidas , Inibidores da Colinesterase/farmacologia , Cymbopogon , Óleos Voláteis , Rhipicephalus/enzimologia , Acaricidas/farmacologia , Acetilcolinesterase , Animais , Larva , Óleos Voláteis/farmacologia
2.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070099

RESUMO

Wild ginseng has better pharmacological effects than cultivated ginseng. However, its industrialization is limited by the inability to grow wild ginseng on a large scale. Herein, we demonstrate how to optimize ginseng production through cultivation, and how to enhance the concentrations of specific ginsenosides through fermentation. In the study, we also evaluated the ability of fermented cultured wild ginseng root extract (HLJG0701-ß) to inhibit acetylcholinesterase (AChE), as well as its neuroprotective effects and antioxidant activity. In invitro tests, HLJG0701-ß inhibited AChE activity and exerted neuroprotective and antioxidant effects (showing increased catalyst activity but decreased reactive oxygen species concentration). In invivo tests, after HLJG0701-ß was orally administered at doses of 0, 125, 250, and 500 mg/kg in an animal model of memory impairment, behavioral evaluation (Morris water maze test and Y-maze task test) was performed. The levels of AChE, acetylcholine (ACh), blood catalase (CAT), and malondialdehyde (MDA) in brain tissues were measured. The results showed that HLJG0701-ß produced the best results at a dose of 250 mg/kg or more. The neuroprotective mechanism of HLJG0701-ß was determined to involve the inhibition of AChE activity and a decrease in oxidative stress. In summary, both invitro and invivo tests confirmed that HJG0701-ß administration can lead to memory improvement.


Assuntos
Antioxidantes/farmacologia , Fermentação , Fármacos Neuroprotetores/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Catalase/sangue , Catalase/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Feminino , Galactose , Ginsenosídeos/farmacologia , Masculino , Malondialdeído/sangue , Camundongos , Teste do Labirinto Aquático de Morris , Ovariectomia , Espécies Reativas de Oxigênio/metabolismo , Escopolamina
3.
Molecules ; 26(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070837

RESUMO

Bioassay-guided separation of young leaves extracts of Syzygium antisepticum (Blume) Merr. & L.M. Perry led to the isolation of four triterpenoids (betulinic acid, ursolic acid, jacoumaric acid, corosolic acid) and one sterol glucoside (daucosterol) from the ethyl acetate extract, and three polyphenols (gallic acid, myricitrin, and quercitrin) from the methanol (MeOH) extract. The MeOH extract of S. antisepticum and some isolated compounds, ursolic acid and gallic acid potentially exhibited acetylcholinesterase activity evaluated by Ellman's method. The MeOH extract and its isolated compounds, gallic acid, myricitrin, and quercitrin, also strongly elicited DPPH radical scavenging activity. In HEK-293 cells, the MeOH extract possessed cellular antioxidant effects by attenuating hydrogen peroxide (H2O2)-induced ROS production and increasing catalase, glutathione peroxidase-1 (GPx-1), and glutathione reductase (GRe). Furthermore, myricitrin and quercitrin also suppressed ROS production induced by H2O2 and induced GPx-1 and catalase production in HEK-293 cells. These results indicated that the young leaves of S. antisepticum are the potential sources of antioxidant and anticholinesterase agents. Consequently, S. antisepticum leaves are one of indigenous vegetables which advantage to promote the health and prevent diseases related to oxidative stress.


Assuntos
Extratos Vegetais/química , Syzygium/química , Acetatos/química , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sequestradores de Radicais Livres/farmacologia , Células HEK293 , Humanos , Metanol/química , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Polifenóis/farmacologia , Syzygium/metabolismo
4.
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
5.
J Med Chem ; 64(10): 6856-6876, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973470

RESUMO

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Grelina/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
6.
J Med Chem ; 64(11): 7483-7506, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34024109

RESUMO

Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3ß: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.


Assuntos
Inibidores da Colinesterase/química , Desenho de Fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Pirimidinonas/química , Tacrina/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Gliceraldeído/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade , Proteínas tau/metabolismo
7.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946559

RESUMO

Alzheimer's disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of -10.03 and -9.00 kcal/mol, respectively. The key residue (His447) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the 'indirubin-AChE' interaction and three H-bonds in the 'dehydroevodiamine-AChE' interaction. These compounds were predicted to cross the blood-brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, 'indirubin-AChE' and 'dehydroevodiamine-AChE' complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.


Assuntos
Acetilcolinesterase/química , Produtos Biológicos/química , Inibidores da Colinesterase/química , Biologia Computacional/métodos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Doença de Alzheimer/tratamento farmacológico , Sítios de Ligação , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Bases de Dados de Produtos Farmacêuticos , Humanos , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
8.
Molecules ; 26(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946788

RESUMO

Despite being widely used traditionally as a general tonic, especially in South East Asia, scientific research on Cassia timoriensis, remains scarce. In this study, the aim was to evaluate the in vitro activities for acetylcholinesterase (AChE) inhibitory potential, radical scavenging ability, and the anti-inflammatory properties of different extracts of C. timoriensis flowers using Ellman's assay, a DPPH assay, and an albumin denaturation assay, respectively. With the exception of the acetylcholinesterase activity, to the best of our knowledge, these activities were reported for the first time for C. timoriensis flowers. The phytochemical analysis confirmed the existence of tannins, flavonoids, saponins, terpenoids, and steroids in the C. timoriensis flower extracts. The ethyl acetate extract possessed the highest phenolic and flavonoid contents (527.43 ± 5.83 mg GAE/g DW and 851.83 ± 10.08 mg QE/g DW, respectively) as compared to the other extracts. In addition, the ethyl acetate and methanol extracts exhibited the highest antioxidant (IC50 20.12 ± 0.12 and 34.48 ± 0.07 µg/mL, respectively), anti-inflammatory (92.50 ± 1.38 and 92.22 ± 1.09, respectively), and anti-AChE (IC50 6.91 ± 0.38 and 6.40 ± 0.27 µg/mL, respectively) activities. These results suggest that ethyl acetate and methanol extracts may contain bioactive compounds that can control neurodegenerative disorders, including Alzheimer's disease, through high antioxidant, anti-inflammatory, and anti-AChE activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cassia/química , Inibidores da Colinesterase/farmacologia , Flores/química , Anti-Inflamatórios/química , Antioxidantes/química , Inibidores da Colinesterase/química , Ativação Enzimática/efeitos dos fármacos , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia
9.
Molecules ; 26(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800212

RESUMO

Mushroom polysaccharides are active medicinal compounds that possess immune-modulatory and anticancer properties. Currently, the mushroom polysaccharides krestin, lentinan, and polysaccharopeptides are used as anticancer drugs. They are an unexplored source of natural products with huge potential in both the medicinal and nutraceutical industries. The northern parts of Pakistan have a rich biodiversity of mushrooms that grow during different seasons of the year. Here we selected an edible Morchella esculenta (true morels) of the Ascomycota group for polysaccharide isolation and characterization. Polysaccharopeptides and polysaccharides from this mushroom were isolated using the green chemistry, hot water treatment method. Fourier transform infrared spectroscopy revealed the sugar nature and possible beta-glucan type structure of these polysaccharides. Antioxidant assays showed that the deproteinized polysaccharides have moderate free radical scavenging activity. These isolated polysaccharides exhibited good acetylcholinesterase (AChE) and butyryl cholinesterase (BChE) inhibition activities. Therefore, these polysaccharides may be valuable for the treatment of Alzheimer's and Parkinson's diseases. Further bioassays are needed to discover the true potential of M. esculenta polysaccharides for medicinal purposes.


Assuntos
Ascomicetos/metabolismo , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Acetilcolinesterase , Agaricales/química , Antineoplásicos/farmacologia , Antioxidantes/química , Ascomicetos/efeitos dos fármacos , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Química Verde/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
10.
ACS Chem Neurosci ; 12(8): 1328-1342, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33797877

RESUMO

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3ß and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and ß-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Glicogênio Sintase Quinase 3 beta , Humanos , Ligantes , Monoaminoxidase/metabolismo
11.
ACS Chem Neurosci ; 12(9): 1698-1715, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852284

RESUMO

Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aß1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.


Assuntos
Doença de Alzheimer , Tacrina , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Camundongos , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Tacrina/farmacologia
12.
ACS Chem Neurosci ; 12(9): 1648-1666, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852798

RESUMO

Cholinesterases are significant biological targets for the regulation of cholinergic neurotransmission, and their inhibitors are being exploited for the management of cognitive decline in various neurological conditions. The 1,4-benzoquinone scaffold possesses antioxidant potential along with AChE inhibition activity in various neurological disorders. To design novel and potent selective 1,4-benzoquinone analogues as cholinesterase inhibitors, a ligand-based drug design strategy was followed to develop a 3D quantitative structure-selectivity relationship (QSSR) model. On the basis of the best fit model, eight novel 1,4-benzoquinone derivatives were designed and synthesized implementing appropriate synthetic procedures and were characterized by various spectral and elemental techniques. All the synthesized compounds were evaluated for their selective in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential at different concentrations using mice brain homogenate as the source of the enzyme. Out of these compounds, the three most selective compounds were further evaluated for behavioral variations using step down passive avoidance and escape learning procedure at a dose of 0.5 mg/kg taking donepezil as the reference drug. Biochemical estimation of the markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, and catalase) has also been carried out to determine the role of the synthesized molecules on the scopolamine induced oxidative damage. Compound 2a displayed appreciable selectivity index values as predicted through the 3D-QSSR model. Further, docked complexes of compound 2a with AChE and BChE were subjected to molecular dynamic simulations for a period of 30 ns to study the orientations and stable conformations of the most active molecules in the catalytic domain of these enzymes. The results obtained from the 3D-QSSR analysis, docking, and molecular dynamic studies were found to be appreciable and provided a deep insight into the structural features required for the selectivity of AChE inhibitors over BChE. The outcome of this study may be used as a novel tool to design new highly selective and more potent molecules.


Assuntos
Acetilcolinesterase , Disfunção Cognitiva , Acetilcolinesterase/metabolismo , Animais , Benzoquinonas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Simulação por Computador , Camundongos , Simulação de Acoplamento Molecular , Estudos Prospectivos , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923726

RESUMO

Alzheimer's disease (AD) is a complex multifactorial disorder, mainly characterized by the progressive loss of memory and cognitive, motor, and functional capacity. The absence of effective therapies available for AD alongside the consecutive failures in the central nervous system (CNS) drug development has been motivating the search for new disease-modifying therapeutic strategies for this disease. To address this issue, the multitarget directed ligands (MTDLs) are emerging as a therapeutic alternative to target the multiple AD-related factors. Following this concept, herein we describe the design, synthesis, and biological evaluation of a family of chromeno[3,4-b]xanthones as well as their (E)-2-[2-(propargyloxy)styryl]chromone precursors, as first-in-class acetylcholinesterase (AChE) and ß-amyloid (Aß) aggregation dual-inhibitors. Compounds 4b and 10 emerged as well-balanced dual-target inhibitors, with IC50 values of 3.9 and 2.9 µM for AChE and inhibitory percentages of 70 and 66% for Aß aggregation, respectively. The molecular docking showed that most of the compounds bound to AChE through hydrogen bonds with residues of the catalytic triad and π-stacking interactions between the main scaffold and the aromatic residues present in the binding pocket. The interesting well-balanced activities of these compounds makes them interesting templates for the development of new multitarget compounds for AD.


Assuntos
Amiloide/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Amiloide/química , Amiloide/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/farmacologia , Cromonas/química , Humanos , Fármacos Neuroprotetores/farmacologia , Ligação Proteica , Multimerização Proteica , Xantonas/química
14.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917200

RESUMO

A series of novel C4-C7-tethered biscoumarin derivatives (12a-e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood-brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer's disease.


Assuntos
Técnicas de Química Sintética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Modelos Moleculares , Células A549 , Doença de Alzheimer/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Cumarínicos/síntese química , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
15.
Molecules ; 26(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926141

RESUMO

The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.


Assuntos
Inibidores da Colinesterase/química , Desenvolvimento de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Ligação Proteica , Relação Estrutura-Atividade
16.
Chem Biol Interact ; 342: 109463, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831382

RESUMO

Memantine is the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It is also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.


Assuntos
Inibidores da Colinesterase/farmacologia , Memantina/farmacologia , Soman/farmacologia , Animais , Bovinos , Inibidores da Colinesterase/química , Dopaminérgicos/farmacologia , Redução da Medicação , Memantina/química , Memantina/metabolismo , Estrutura Molecular , Fatores de Tempo
17.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806197

RESUMO

The acetylcholinesterase (AChE) inhibitors are the main drugs for symptomatic treatment of neurodegenerative disorders like Alzheimer's disease. A recently designed, synthesized and tested hybrid compound between the AChE inhibitor galantamine (GAL) and the antioxidant polyphenol curcumin (CU) showed high AChE inhibition in vitro. Here, we describe tests for acute and short-term toxicity in mice as well as antioxidant tests on brain homogenates measured the levels of malondialdehide (MDA) and glutathione (GSH) and in vitro DPPH, ABTS, FRAP and LPO inhibition assays. Hematological and serum biochemical analyses were also performed. In the acute toxicity tests, the novel AChE inhibitor given orally in mice showed LD50 of 49 mg/kg. The short-term administration of 2.5 and 5 mg/kg did not show toxicity. In the ex vivo tests, the GAL-CU hybrid performed better than GAL and CU themselves; in a dose of 5 mg/kg, it demonstrates 25% reduction in AChE activity, as well as a 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The antioxidant activity of 4b measured ex vivo was proven in the in vitro tests. In the ABTS assay, 4b showed radical scavenging activity 10 times higher than the positive control butylhydroxy toluol (BHT). The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a prospective multitarget drug candidate for treatment of neurodegenerative disorders.


Assuntos
Encéfalo/metabolismo , Inibidores da Colinesterase , Curcumina , Galantamina , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Encéfalo/patologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Curcumina/análogos & derivados , Curcumina/química , Curcumina/farmacologia , Modelos Animais de Doenças , Feminino , Galantamina/análogos & derivados , Galantamina/química , Galantamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia
18.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915968

RESUMO

Neurodegenerative diseases, for example Alzheimer's, are perceived as driven by hereditary, cellular, and multifaceted biochemical actions. Numerous plant products, for example flavonoids, are documented in studies for having the ability to pass the blood-brain barrier and moderate the development of such illnesses. Computer-aided drug design (CADD) has achieved importance in the drug discovery world; innovative developments in the aspects of structure identification and characterization, bio-computational science, and molecular biology have added to the preparation of new medications towards these ailments. In this study we evaluated nine flavonoid compounds identified from three medicinal plants, namely T. diversifolia, B. sapida, and I. gabonensis for their inhibitory role on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) activity, using pharmacophore modeling, auto-QSAR prediction, and molecular studies, in comparison with standard drugs. The results indicated that the pharmacophore models produced from structures of AChE, BChE and MAO could identify the active compounds, with a recuperation rate of the actives found near 100% in the complete ranked decoy database. Moreso, the robustness of the virtual screening method was accessed by well-established methods including enrichment factor (EF), receiver operating characteristic curve (ROC), Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC), and area under accumulation curve (AUAC). Most notably, the compounds' pIC50 values were predicted by a machine learning-based model generated by the AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best models achieved for AChE, BChE and MAO were models kpls_radial_17 (R2 = 0.86 and Q2 = 0.73), pls_38 (R2 = 0.77 and Q2 = 0.72), kpls_desc_44 (R2 = 0.81 and Q2 = 0.81) and these externally validated models were utilized to predict the bioactivities of the lead compounds. The binding affinity results of the ligands against the three selected targets revealed that luteolin displayed the highest affinity score of -9.60 kcal/mol, closely followed by apigenin and ellagic acid with docking scores of -9.60 and -9.53 kcal/mol, respectively. The least binding affinity was attained by gallic acid (-6.30 kcal/mol). The docking scores of our standards were -10.40 and -7.93 kcal/mol for donepezil and galanthamine, respectively. The toxicity prediction revealed that none of the flavonoids presented toxicity and they all had good absorption parameters for the analyzed targets. Hence, these compounds can be considered as likely leads for drug improvement against the same.


Assuntos
Descoberta de Drogas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Relação Quantitativa Estrutura-Atividade , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Sítios de Ligação , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Ligantes , Conformação Molecular , Estrutura Molecular , Ligação Proteica
19.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916300

RESUMO

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Inibidores da Colinesterase/isolamento & purificação , Furanos/química , Furanos/farmacologia , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Relação Estrutura-Atividade
20.
Mar Drugs ; 19(3)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800819

RESUMO

Chemical investigation of the South-Pacific marine sponge Suberea clavata led to the isolation of eight new bromotyrosine metabolites named subereins 1-8 (2-9) along with twelve known co-isolated congeners. The detailed configuration determination of the first representative major compound of this family 11-epi-fistularin-3 (11R,17S) (1) is described. Their chemical characterization was achieved by HRMS and integrated 1D and 2D NMR (nuclear magnetic resonance) spectroscopic studies and extensive comparison with literature data. For the first time, a complete assignment of the absolute configurations for stereogenic centers C-11/17 of the known members (11R,17S) 11-epi-fistularin-3 (1) and 17-deoxyfistularin-3 (10) was determined by a combination of chemical modifications, Mosher's technology, and ECD spectroscopy. Consequently, the absolute configurations of all our new isolated compounds 2-9 were determined by the combination of NMR, Mosher's method, ECD comparison, and chemical modifications. Interestingly, compounds 2-7 were obtained by chemical transformation of the major compound 11-epi-fistularin-3 (1). Evaluation for acetylcholinesterase inhibition (AChE), DNA methyltransferase 1 (DNMT1) modulating activity and antifouling activities using marine bacterial strains are also presented.


Assuntos
Poríferos/metabolismo , Tirosina/análogos & derivados , Animais , Incrustação Biológica/prevenção & controle , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , DNA (Citosina-5-)-Metiltransferase 1/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Espectroscopia de Ressonância Magnética , Oceano Pacífico , Tirosina/química , Tirosina/isolamento & purificação , Tirosina/farmacologia
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