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1.
J Mol Graph Model ; 116: 108265, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35816907

RESUMO

Acetylcholinesterase (AChE) is the object of many studies due to the fact that it plays an important role in the vital activity of organisms. In particular, when new AChE inhibitors are developed, much attention is paid to the specificity of their action. One of the approaches used to study the specificity is to compare AChE taken from various organisms. In this work, crystallographic data are used to investigate the active sites of AChE (ASAs) in the free (uncomplexed) state for the following five organisms: Homo sapiens (HS), Mus musculus (MM), Torpedo californica (TC), Electrophorus electricus (EE), and Drosophila melanogaster (DM). The structural fractal analysis (SFA) proposed by us earlier is used as a research method. This method is based on the calculation and comparison of the fractal dimensions of molecular structures. SFA demonstrates that there are no significant structural differences between the active sites of human AChE and other AChEs. However, differences are found for the MM/EE pair. Further analysis of individual AARs has revealed two different areas of active sites. Ser203, Trp236, Phe338, and Tyr341 are found to belong to a variable region, and the remaining AARs belong to a conservative region of the ASAs. The fraction of "variability" is low, 0.8%.


Assuntos
Acetilcolinesterase , Fractais , Acetilcolinesterase/química , Animais , Domínio Catalítico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Drosophila melanogaster , Electrophorus/metabolismo , Humanos , Camundongos , Torpedo/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-35843445

RESUMO

The inhibitory effects of bisphenol A (BPA) and bisphenol S (BPS), which are common pollutants, especially in marine and freshwater, on the electric eel acetylcholinesterase (AChE) activity were studied in vitro and in silico. Both produced full non-competitive inhibition, but the Ki value of BPA was half that of BPS. Molecular docking analyses revealed that both interact with residues W286, F297, Y337, F338 in the PAS and ABS regions in the middle and entrance of the active site gorge, and that BPS also has hydrogen bond with S203 of the catalytic triad. The surge at IC50 values of both compounds with an inflection point at pH: 8.2 suggested that Y124 and/or Y337 in the narrow gorge are primary structural factors in binding. Less effective inhibition of BPS, especially at 25-30 °C, the temperature at which enzyme activity peaks, was attributed to the conformation of the narrow gorge. Homology analyses for AChE initially revealed a significant degree of identity, particularly in the alpha/beta hydrolase domain, which also comprises the active site, with sequences from seven distinct teleost species of various environments. Finally, it was discovered for the first time that BPS, like BPA, is a significant inhibitor of AChE, and this was confirmed by in vitro and in silico analyses done at various pH and temperature levels. It was concluded that this effect might also apply to AChE of most other bony fish.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Animais , Compostos Benzidrílicos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Electrophorus/metabolismo , Simulação de Acoplamento Molecular , Fenóis
3.
Org Biomol Chem ; 20(28): 5589-5601, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35796650

RESUMO

The management of neurological disorders such as dementia associated with Alzheimer's or Parkinson's disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. Fourteen small inhibitors were designed based on recent discoveries about the inhibitory potential of a range of related marine secondary metabolites. The compounds were evaluated, in kinetic enzymatic assays, for their ability to inhibit three different cholinesterase enzymes and it was shown that compounds with a high inhibitory activity towards electric eel and human recombinant acetylcholinesterase (IC50 between 20-70 µM) could be prepared. It was also shown that this compound class was particularly active against horse serum butyrylcholinesterase, with IC50 values between 0.8-16 µM, which is an order of magnitude more potent than the clinically used positive control neostigmine. The compounds were further tested for off-target toxicity against both human umbilical vein endothelial cells and bovine and human erythrocytes and were shown to display a low mammalian cellular toxicity. Overall, the study illustrates how the brominated dipeptide marine pharmacophore can be used as a versatile natural scaffold for the design of potent, and selective cholinesterase inhibitors.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Bovinos , Inibidores da Colinesterase/química , Electrophorus , Células Endoteliais/metabolismo , Cavalos , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
4.
ChemMedChem ; 17(8): e202100721, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35157366

RESUMO

Structure-based virtual screening of the Enamine database of 1.7 million compounds followed by WaterMap calculations (a molecular-dynamics-simulation-based method) was applied to identify novel acetylcholinesterase (AChE) inhibitors. The inhibitory potency of 29 selected compounds against electric eel (ee) AChE was determined using Ellman's method. Three compounds were found to be active (success rate 10 %). For the most potent compound (∼40 % inhibition at 10 µM), 20 derivatives were discovered based on the Enamine similarity search. Finally, five compounds were found to be promising (IC50 ranged from 6.3 µM to 17.5 µM) inhibitors of AChE. The performed similarity and fragment analysis confirmed significant structural novelty for these AChE inhibitors. Toxicity/safety of selected compounds was determined in zebrafish model.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Acetilcolinesterase/química , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Electrophorus , Simulação de Acoplamento Molecular , Peixe-Zebra
5.
Bioorg Med Chem ; 58: 116660, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35183029

RESUMO

Based on the multitarget-directed ligands strategy, a series of 3-butyl-6-benzyloxyphthalide Mannich base derivatives were designed, synthesized and identified for Alzheimer's disease (AD). Biological activity studies demonstrated that the designed hybrids showed multitarget activities toward AD. Among them, compound 7d was the most potent agent with excellent inhibitory activities on EeAChE (IC50 = 0.087 µM), HuAChE (IC50 = 0.041 µM) and MAO-B (IC50 = 0.30 µM). Furthermore, molecular docking studies were conducted to investigate the interaction mode with enzymes. Besides, 7d also possessed good effects of Cu2+ chelation, ameliorate oxidative stress, and anti-neuroinflammation, desirable BBB permeability and eligible drug-like properties. Altogether, the multifunctional profiles of 7d prove that it deserves further investigation as a novel drug candidate for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Bases de Mannich/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Bases de Mannich/síntese química , Bases de Mannich/química , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
6.
Artigo em Inglês | MEDLINE | ID: mdl-35030473

RESUMO

A sensitive assay was developed to evaluate inhibitory effects of aqueous solution on acetylcholinesterase (AChE) activity via measuring hydrolysis rates of acetylcholine (ACh) based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Upon having identified precursor ions and product ions of the ACh and its hydrolysis products choline (Ch), the separation chromatogram for these two analytes has been established using a 50 mm reverse-phase BEH Shield RP18 column. The total chromatographic separation time is 7 min; limits of detection (LODs) for ACh and Ch are 0.14 µg L-1 and 0.12 µg L-1, respectively. A simple method for inactivation of AChE and optimization of operational parameters were then sequentially performed. It was found that adjusting solution pH to 2.5 not only can terminate the enzymatic reaction but also solve band shifting and broadening caused by aqueous matrices in chromatographic separation during UPLC-MS/MS detection. Under conditions of 0.00075 U mL-1 AChE, initial concentration of ACh at 100 µg L-1 and 20 min observation time, IC50 values of the proposed assay for chlorpyrifos-oxon, diazoxon, malaoxon, methidathion oxon, omethoate and paraoxon were 3.5 nM, 16.8 nM, 2.4 nM, 6.8 nM, 270 nM and 36.9 nM, respectively. They are 4.5-51.9 times smaller than those reported in a LC-MS based method, and >120 times lower than those obtained by the traditional Ellman method. The results suggested that, the proposed assay significantly increases the sensitivity of commercial AChE. In addition, inhibition efficiencies of three surface waters, a groundwater and four commercial brands of bottled drinking water samples on AChE activity were firstly measured using this UPLC-MS/MS based method. These water samples were proved to have different inhibitory effects on AChE activity, and the inhibition efficiencies dependent on concentrations of dissolved organic carbon (DOC) but are independent of UV absorbance at 254 nm (UV254) values. These results indicate that the proposed method has advantages of high sensitivity over all other conventional methods. It may become a promising AChE inhibition assay for assessing toxicity of aqueous solution containing neurotoxicity contaminants such as organophosphorus pesticides (OPPs) at low levels, or used to evaluate potential inhibition effects of natural waters on AChE activity.


Assuntos
Inibidores da Colinesterase/química , Cromatografia Líquida de Alta Pressão/métodos , Proteínas de Peixes/antagonistas & inibidores , Espectrometria de Massas em Tandem/métodos , Poluentes da Água/química , Acetilcolina/química , Acetilcolinesterase/química , Animais , Água Potável/química , Electrophorus , Água Subterrânea/química , Hidrólise , Compostos Organofosforados/química , Sensibilidade e Especificidade
7.
Mol Divers ; 26(3): 1455-1479, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34328603

RESUMO

Structure-based drug design (SBDD) is an important in silico technique, used for the identification of enzyme inhibitors. Acetylcholinesterase (AChE), obtained from Electrophorus electricus (ee), is widely used for the screening of AChE inhibitors. It shares structural homology with the AChE of human and other organisms. Till date, the three-dimensional crystal structure of enzyme from ee is not available that makes it challenging to use the SBDD approach for the identification of inhibitors. A homology model was developed for eeAChE in the present study, followed by its structural refinement through energy minimisation. The docking protocol was developed using a grid dimension of 84 × 66 × 72 and grid point spacing of 0.375 Å for eeAChE. The protocol was validated by redocking a set of co-crystallised inhibitors obtained from mouse AChE, and their interaction profiles were compared. The results indicated a poor performance of the Autodock scoring function. Hence, a batch of machine learning-based scoring functions were developed. The validation results displayed an accuracy of 81.68 ± 1.73% and 82.92 ± 3.05% for binary and multiclass classification scoring function, respectively. The regression-based scoring function produced [Formula: see text] and [Formula: see text] values of 0.94, 0.635 and 0.634, respectively.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Acetilcolinesterase/química , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Electrophorus , Aprendizado de Máquina , Camundongos
8.
Arch Pharm (Weinheim) ; 355(2): e2100376, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34862640

RESUMO

The identification of novel compounds that can inhibit physiologically and metabolically important drug targets or enzymes has prime importance in medicinal chemistry. With this aim, a range of secnidazole esters 1-30 were synthesized under the heading of biology-oriented drug synthesis by the 1,1'-carbonyldiimidazole-mediated coupling reaction between secnidazole and varyingly benzoic acid derivatives. All compounds were screened for inhibitory activity against human carbonic anhydrase (hCA) I and II, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The results indicate that all the synthesized compounds showed potent inhibitory activities against all targets, as compared to the standard inhibitors, revealed by IC50 values. Ki values of the secnidazole derivatives 1-30 for hCA I, hCA II, AChE, BChE, and α-glucosidase enzymes were obtained in the ranges of 47.37-190.74, 44.38-198.21, 12.14-68.37, 8.04-61.53, and 7.78-45.91 nM, respectively. To assess the enzyme-ligand interactions, the optimized most active compounds 2, 3, 8, 9, 14, 17, and 23 were subjected to molecular docking studies with modeled AChE, BChE, hCA I, hCA II, and α-glucosidase enzymes, where several important and key interactions were monitored with amino acid residues of each target enzyme.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Metronidazol/análogos & derivados , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Ésteres , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Cavalos , Humanos , Concentração Inibidora 50 , Ligantes , Metronidazol/síntese química , Metronidazol/química , Metronidazol/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 228: 114031, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34875520

RESUMO

Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC50 value of 0.57 µM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on H2O2-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 µM, as well as selectively metal chelating properties via chelating Cu2+. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.


Assuntos
Acetofenonas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Oximas/farmacologia , Acetofenonas/síntese química , Acetofenonas/química , Acetilcolinesterase/metabolismo , Animais , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Electrophorus , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Oximas/síntese química , Oximas/química , Picratos/antagonistas & inibidores , Ratos , Relação Estrutura-Atividade
10.
J Biochem Mol Toxicol ; 36(2): e22952, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34783117

RESUMO

Four new and four known isoxazoline derivatives were synthesized from the reactions of benzonorbornadiene with nitrile oxides formed from the corresponding benzaldehydes. Three new and one known pyrazoline derivatives were also synthesized from the reactions of the benzonorbornadiene with nitrile imines formed from the corresponding compounds. The synthesized nitrogen-based novel heterocyclic compounds were evaluated against the human carbonic anhydrase isoenzymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The synthesized nitrogen-based novel heterocyclic compounds showed IC50 values in the range of 2.69-7.01 against hCA I, 2.40-4.59 against hCA II, 0.81-1.32 µM against AChE, and 20.83-1.70 µM against BChE enzymes. On the contrary, nitrogen-based novel heterocyclic compounds demonstrated Ki values between 2.93 ± 0.59-8.61 ± 1.39 against hCA I, 2.05 ± 0.62-4.97 ± 0.95 against hCA II, 0.34 ± 0.02-0.92 ± 0.17 nM against AChE, and 0.50 ± 0.04-1.20 ± 0.16 µM against BChE enzymes. The synthesized nitrogen-based novel heterocyclic compounds exhibited effective inhibition profiles against both indicated metabolic enzymes. These results may contribute to the development of new drugs particularly to treat some disorders, which are widespread in the world including glaucoma and Alzheimer's diseases.


Assuntos
Acetilcolinesterase , Butirilcolinesterase/química , Anidrase Carbônica II , Anidrase Carbônica I , Inibidores da Anidrase Carbônica , Acetilcolinesterase/química , Animais , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/química , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Relação Estrutura-Atividade
11.
Mol Pharmacol ; 101(3): 154-167, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34969831

RESUMO

Alzheimer's disease is a multifactorial neurodegenerative disorder. Since cholinergic deficit is a major factor in this disease, two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChRs). Given that caffeine is a natural compound that behaves as an AChE inhibitor and as a partial agonist of nAChRs, the aim of this work was to synthetize more potent bifunctional caffeine analogs that modulate these two molecular targets. To this end, a theophylline structure was connected to a pyrrolidine structure through a methylene chain of different lengths (3 to 7 carbon atoms) to give compounds 7-11 All caffeine derivatives inhibited the AChE, of which compound 11 showed the strongest effect. Electrophysiological studies showed that all compounds behave as agonists of the muscle and the neuronal α7 nAChR with greater potency than caffeine. To explore whether the different analogs could affect the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) was used. Compounds 9 and 10 conduced the nAChR to a different conformational state comparable with a control nAChR desensitized state. Finally, molecular docking experiments showed that all derivatives interacted with both the catalytic and anionic sites of AChE and with the orthosteric binding site of the nAChR. Thus, the new synthetized compounds can inhibit the AChE and activate muscle and α7 nAChRs with greater potency than caffeine, which suggests that they could be useful leaders for the development of new therapies for the treatment of different neurologic diseases. SIGNIFICANCE STATEMENT: In this work we synthetized caffeine derivatives which can inhibit acetylcholinesterase and activate both muscle and α7 nicotinic acetylcholine receptors (nAChRs) with higher potency than caffeine. These analogs can be divided into two groups: a non-desensitizing and a desensitizing nAChR group. From the nAChR non-desensitizing group, we propose compound 11 as the most interesting analog for further studies since it inhibits acetylcholinesterase with the highest potency and activates the nAChRs in the picomolar range without inducing receptor desensitization.


Assuntos
Cafeína/análogos & derivados , Cafeína/síntese química , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Cafeína/metabolismo , Cafeína/farmacologia , Electrophorus , Células HEK293 , Humanos , Simulação de Acoplamento Molecular/métodos , Estrutura Secundária de Proteína , Torpedo , Receptor Nicotínico de Acetilcolina alfa7/química
12.
J Enzyme Inhib Med Chem ; 37(1): 69-85, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34894968

RESUMO

A novel series of chalcone-Vitamin E-donepezil hybrids was designed and developed based on multitarget-directed ligands (MTDLs) strategy for treating Alzheimer's disease (AD). The biological results revealed that compound 17f showed good AChE inhibitory potency (ratAChE IC50 = 0.41 µM; eeAChE IC50 = 1.88 µM). Both the kinetic analysis and docking study revealed that 17f was a mixed type AChE inhibitor. 17f was also a good antioxidant (ORAC = 3.3 eq), selective metal chelator and huMAO-B inhibitor (IC50 = 8.8 µM). Moreover, it showed remarkable inhibition of self- and Cu2+-induced Aß1-42 aggregation with a 78.0 and 93.5% percentage rate at 25 µM, respectively, and disassembled self-induced and Cu2+-induced aggregation of the accumulated Aß1-42 fibrils with 72.3 and 84.5% disaggregation rate, respectively. More importantly, 17f exhibited a good neuroprotective effect on H2O2-induced PC12 cell injury and presented good blood-brain barrier permeability in vitro. Thus, 17f was a promising multi-target-directed ligand for treating AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Chalcona/química , Chalcona/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Ligantes , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Vitamina E/química , Vitamina E/farmacologia
13.
Eur J Med Chem ; 227: 113947, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34731766

RESUMO

Triterpenoic acids (oleanolic, ursolic, betulinic, platanic and glycyrrhetinic acid) were acetylated and coupled with 1,3- or 1,4-diazabicyclo[3.2.2]nonanes to yield amides. Reaction of these amides with methyl iodide at the distal nitrogen of the bicyclic system gave the corresponding quaternary ammonium salts. These compounds were shown to act as excellent inhibitors of the enzyme butyrylcholinesterase (BChE) while being only weak inhibitors for acetylcholinesterase (AChE). Evaluation of the enzyme kinetics revealed these compounds to act as hyperbolic inhibitors for BChE while the results from molecular modeling gave an explanation for their selectivity between AChE and BChE.


Assuntos
Compostos Aza/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Triterpenos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Compostos Aza/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Metilação , Estrutura Molecular , Relação Estrutura-Atividade , Torpedo , Triterpenos/síntese química , Triterpenos/química
14.
Molecules ; 26(23)2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34885880

RESUMO

Screening the lead compounds which could interact both with PAS and CAS of acetylcholinesterase (AChE) is an important trend in finding innovative drugs for Alzheimer's disease (AD). In this paper, four sesquiterpenes, i.e., atractylenolide III (1), atractylenolide IV (2), 3-acetyl-atractylon (3) and ß-eudesmol (4), were obtained from the wild Atractylode macrocephala grown in Qimen for the first time. Their structures were elucidated mainly by NMR spectroscopy. To screen the potential dual site inhibitors of AChE, the compounds 1, 2, 3, as well as a novel and rare bisesquiterpenoid lactone, biatractylenolide II (5), which was also obtained from the tilted plant in our previous investigation, were evaluated their AChE inhibitory activities by using Ellman's colorimetric method. The results showed that biatractylenolide II displayed moderate inhibitory activity (IC50 = 19.61 ± 1.11 µg/mL) on AChE. A further molecular docking study revealed that biatractylenolide II can interact with both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. These data suggest that biatractylenolide II can be considered a new lead compound to research and develop more potential dual site inhibitors of AChE.


Assuntos
Acetilcolinesterase/metabolismo , Atractylodes/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Animais , Electrophorus , Simulação de Acoplamento Molecular
15.
Molecules ; 26(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34771145

RESUMO

Two rare guanidine-type alkaloids, Buthutin A (1) and Buthutin B (2), along with two other compounds (3, 4), were isolated from Buthus martensii Karsch, and determined using extensive spectroscopic data analysis and high resolution-mass spectrometry. Compound 1 showed the most potent inhibition on AChE and BChE with IC50 values of 7.83 ± 0.06 and 47.44 ± 0.95 µM, respectively. Kinetic characterization of compound 1 confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows its interaction with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of compound 1 to PAS domain of AChE was also confirmed experimentally. Moreover, compounds 1 and 3 exhibited satisfactory biometal binding abilities toward Cu2+, Fe2+, Zn2+ and Al3+ ions. These results provide a new evidence for further development and utilization of B. martensii in health and pharmaceutical products.


Assuntos
Inibidores da Colinesterase/farmacologia , Complexos de Coordenação/farmacologia , Descoberta de Drogas , Guanidinas/farmacologia , Escorpiões/química , Acetilcolinesterase/metabolismo , Alumínio/química , Alumínio/farmacologia , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Complexos de Coordenação/química , Complexos de Coordenação/isolamento & purificação , Electrophorus , Guanidinas/química , Guanidinas/isolamento & purificação , Cavalos , Metais Pesados/química , Metais Pesados/farmacologia , Estrutura Molecular
16.
Eur J Med Chem ; 225: 113792, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34530376

RESUMO

The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and ß-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Aß aggregation (53% at 10 µM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenvolvimento de Medicamentos , Fármacos Neuroprotetores/farmacologia , Receptores de Serotonina/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Electrophorus , Células Hep G2 , Cavalos , Humanos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade
17.
Bioorg Chem ; 116: 105301, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34492558

RESUMO

A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.


Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/farmacologia , Pargilina/análogos & derivados , Propilaminas/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Células Cultivadas , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Relação Dose-Resposta a Droga , Electrophorus , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Cavalos , Humanos , Masculino , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Pargilina/síntese química , Pargilina/química , Pargilina/farmacologia , Propilaminas/síntese química , Propilaminas/química , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
18.
Comput Biol Chem ; 94: 107565, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34474201

RESUMO

A series of novel urea, sulfamide and N,N-dipropargyl substituted benzylamines were synthesized from dihydrochalcones. The synthesized compounds were evaluated for their cholinesterases and carbonic anhydrase inhibitory actions. The known dihydrochalcones were converted into four new benzylamines via reductive amination. N,N-Dipropargylamines, ureas and sulfamides were synthesized following the reactions of benzylamines with propargyl bromide, N,N-dimethyl sulfamoyl chloride and N,N-dimethyl carbamoyl chloride. The novel substituted benzylamines derived from dihydrochalcones were evaluated against some enzymes such as human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The novel substituted benzylamines derived from dihydrochalcones exhibited Ki values in the range of 0.121-1.007 nM on hCA I, and 0.077-0.487 nM on hCA II closely related to several pathological processes. On the other hand, Ki values were found in the range of 0.112-0.558 nM on AChE, 0.061-0.388 nM on BChE. As a result, novel substituted benzylamines derived from dihydrochalcones showed potent inhibitory profiles against indicated metabolic enzymes. In addition, Induced-Fit Docking (IFD) simulations and ADME prediction studies have also been carried out to elucidate the inhibition mechanisms and drug-likeness of the synthesized compounds. Therefore, these results can make significant contributions to the treatment of some global diseases, especially Alzheimer's diseases and glaucoma, and the development of new drugs.


Assuntos
Benzilaminas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Benzilaminas/síntese química , Benzilaminas/química , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
19.
ChemMedChem ; 16(21): 3315-3325, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34342141

RESUMO

Reversible acetylcholinesterase (AChE) inhibitors are key therapeutic tools to modulate the cholinergic connectivity compromised in several degenerative pathologies. In this work, four alkyl esters of homarine were synthesized and screened by using Electrophorus electricus AChE and rat brain AChE-rich fraction. Results showed that all homarine alkyl esters are able to inhibit AChE by a competitive inhibition mode. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HO-C16 (IC50 =7.57±3.32 µM and Ki =18.96±2.28 µM) the most potent inhibitor. The fluorescence quenching studies confirmed that HO-C16 is the compound with higher selectivity and affinity for the tryptophan residues in the catalytic active site of AChE. Preliminary cell viability studies showed that homarine esters display no toxicity for human neuronal SH-SY5Y cells. Thus, the long-chain homarine esters emerge as new anti-cholinesterase agents, with potential to be considered for therapeutic applications development.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ésteres/farmacologia , Ácidos Picolínicos/farmacologia , Animais , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Ésteres/síntese química , Ésteres/química , Humanos , Modelos Moleculares , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ratos , Relação Estrutura-Atividade
20.
Chem Pharm Bull (Tokyo) ; 69(8): 811-816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334527

RESUMO

Three new aconitine-type C19-diterpenoid alkaloid namely novolunines A (1), B (2), and C (3), along with fifteen known diterpenoid alkaloids were isolated from the roots of Aconitum novoluridum, whose phytochemical investigations have never been reported before. The structures of three new alkaloids were established on the basis of spectra data (high-resolution electrospray ionization (HR-ESI)-MS, IR, one dimensional (1D)- and 2D-NMR). Noteworthily, novolunines A (1) and B (2) are two diterpenoid alkaloids bearing conformational isomerism. In addition, the diterpenoid alkaloids 1-3 did not show any anti-acetylcholinesterase (AChE) or anti-inflammatory activities.


Assuntos
Acetilcolinesterase/metabolismo , Aconitum/química , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Electrophorus , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7
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