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1.
Eur J Med Chem ; 197: 112282, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380361

RESUMO

Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC50 = 7.31 µM), BChE (IC50 = 0.56 µM) and MAO-B (IC50 = 26.1 µM) inhibitor 10, dual AChE (IC50 = 2.25 µM) and BChE (IC50 = 0.81 µM) inhibitor 22, selective BChE (IC50 = 0.06 µM) inhibitor 13, and selective MAO-B (IC50 = 0.18 µM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid ß1-42 (Aß1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aß1-42 anti-aggregation effects.


Assuntos
Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Butirilcolinesterase/metabolismo , Carbamatos/síntese química , Carbamatos/toxicidade , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/toxicidade , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Fragmentos de Peptídeos/metabolismo , Piperidinas/síntese química , Piperidinas/toxicidade , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
2.
J Enzyme Inhib Med Chem ; 35(1): 805-814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183602

RESUMO

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 µM) is similar to the positive drug donepezil (0.059 ± 0.003 µM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ansiolíticos/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Picratos/antagonistas & inibidores , Ratos , Ratos Wistar , Relação Estrutura-Atividade
3.
Sci Rep ; 10(1): 3014, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080261

RESUMO

A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Isoxazóis/uso terapêutico , Receptores 5-HT4 de Serotonina/metabolismo , Doença de Alzheimer/patologia , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Donepezila/química , Donepezila/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular
4.
Eur J Med Chem ; 191: 112140, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088494

RESUMO

2,3-Dihydro-5,6-dimethoxy-2-[4-(4-alkyl-4-methylpiperazinium-1-yl)benzylidine]-1H-inden-1-one halide salt derivatives as a novel donepezil hybrid analogs with the property of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme inhibition were designed and synthesized via N-alkylation reaction of 2,3-dihydro-5,6-dimethoxy-2-[4-(4-methylpiperazin-1-yl)benzylidene]-1H-inden-1-one with some alkyl halides. Biological tests demonstrated that most of the synthesized compounds have moderate to good inhibitory activities effect on cholinesterase enzymes. Among them, 10e showed the best profile as a selected compound for inhibition of hAChE (IC50 = 0.32) and hBuChE (IC50 = 0.43 µM) enzymes. Kinetic analysis and molecular docking led to a better understanding of this compound. Kinetic studies disclosed that 10e inhibited acetylcholinesterase in mixed-type and butyrylcholinesterase in non-competitive type. The toxicity results showed that 10e is less toxic than donepezil and has better inhibitory activity against hBuChE when compared to donepezil or Galantamine. Other performed experiments revealed that 10e has an anti-ß amyloid effect which is capable of reducing ROS, LDH and MDA also possing positive effect on TAC. On the other hand, it has shown a good anti-inflammation effect.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Indenos/farmacologia , Piperazinas/farmacologia , Acetilcolinesterase/genética , Algoritmos , Butirilcolinesterase/genética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Indenos/síntese química , Indenos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade
5.
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
6.
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
7.
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
8.
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
9.
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
10.
Eur J Med Chem ; 187: 111958, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865014

RESUMO

Here we reported novel apigenin-rivastigmine hybrids were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, their activity in vitro results revealed that compound 3d showed significant antioxidant potency (ORAC = 1.3 eq), and it was a reversible huAChE (IC50 = 6.8 µM) and huBChE (IC50 = 16.1 µM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated Aß1-42 aggregation, and also inhibited hAChE-mediated induced Aß1-40 aggregation. Compound 3d exhibited remarkable neuroprotective effect and hepatoprotective activity. In addition, compound 3d presented favourable blood-brain barrier penetration in vitro and drug-like property. Further, the in vivo assay displayed that 3d indicated remarkable dyskinesia recovery rate and response efficiency on AD zebrafish, and exhibited surprising protective effect on Aß1-40-mediated zebrafish vascular injury. More importantly, 3d did not indicate obvious acute toxicity at dose up to 2000 mg/kg, and could improve scopolamine-induced memory impairment. Subsequently, the regulation of multi-targets for 3d were further confirmed through transcriptome sequencing of brain hippocampi, which also offered novel potential targets and opened a new way to treat Alzheimer's disease. More interestingly, the metabolism of 3din vitro indicated that 4 metabolites in rat liver microsome metabolism, 2 metabolites in human liver microsome metabolism, and 4 metabolites in intestinal flora metabolism, which offered supports for the preclinical study of 3d. Overall, this study exhibited that compound 3d was a promising advanced compound targeted multiple factors associated with AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Apigenina/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Apigenina/química , Apigenina/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Ratos , Rivastigmina/química , Rivastigmina/metabolismo , Relação Estrutura-Atividade , Peixe-Zebra
11.
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
12.
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
13.
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
14.
Neurochem Res ; 45(2): 241-253, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31845170

RESUMO

This work evaluated the in vitro effect of thiazolidin-4-ones on the activity of AChE (total and isoforms) isolated from the cerebral cortex, hippocampus, and lymphocytes. Kinetic parameters were evaluated and molecular docking was performed. Our results showed that thiazolidinones derived from 4-(methylthio)benzaldehyde (1) and from 4-(methylsulfonyl)benzaldehyde (2) were capable of inhibiting the AChE activity in vitro. Three compounds, two with a propylpiperidine (1b and 2b) moiety and one with a 3-(diethylamino)propyl (1c) moiety showed IC50 values of 13.81 µM, and 3.13 µM (1b), 55.36 µM and 44.33 µM (1c) for cerebral cortex and hippocampus, respectively, and 3.11 µM for both (2b). Enzyme kinetics revealed that the type of AChE inhibition was mixed. Compound 1b inhibited the G1 and G4 AChE isoforms, while compounds 1c and 2b selectively inhibited the G4 isoform. Molecular docking showed a possible three-dimensional fit into the enzyme. Our findings showed that these thiazolidin-4-ones, especially those containing the propylpiperidine core, have a potential cholinesterase inhibitory activity and can be considered good candidates for future Alzheimer's therapy.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Tiazolidinas/farmacologia , Acetilcolinesterase/química , Animais , Domínio Catalítico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Hipocampo/efeitos dos fármacos , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Cinética , Linfócitos/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Ratos Wistar , Tiazolidinas/síntese química , Tiazolidinas/metabolismo
15.
Eur J Med Chem ; 185: 111785, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669851

RESUMO

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H3 receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against H3R and both enzymes. Two derivatives were chosen - 5 (IC50 = 0.46 µM (AChE); 0.44 µM (BuChE); Ki = 159.8 nM (H3R)) and 17 (IC50 = 0.50 µM (AChE); 0.76 µM (BuChE); Ki = 228.2 nM (H3R)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Cavalos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-Atividade
16.
Pak J Pharm Sci ; 32(5): 2091-2098, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31813875

RESUMO

With the recent research advances in molecular biology and technology multiple credible hypotheses about the progress of Alzheimer's disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop muilti-functional agents, which can mainly serve as dual beta-secretase (BACE 1) and Acetylcholinesterase (AChE) inhibitors. Series of new compounds were designed, synthesized and evaluated in this work, from which we identified 2-((4-(1,3-dioxoisoindolin-2-yl)benzyl)amino)-2-oxoethyl-2-(4-methoxyphenyl)acetate (1h) as a new dual cholinesterase and beta-secretase inhibitor without toxicity.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Ligantes
17.
Int J Mol Sci ; 21(1)2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861333

RESUMO

A series of 44 hybrid compounds that included in their structure tetrahydroquinoline (THQ) and isoxazole/isoxazoline moieties were synthesized through the 1,3-dipolar cycloaddition reaction (1,3-DC) from the corresponding N-allyl/propargyl THQs, previously obtained via cationic Povarov reaction. In vitro cholinergic enzymes inhibition potential of all compounds was tested. Enzyme inhibition assays showed that some hybrids exhibited significant potency to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Especially, the hybrid compound 5n presented the more effective inhibition against AChE (4.24 µM) with an acceptable selectivity index versus BChE (SI: 5.19), while compound 6aa exhibited the greatest inhibition activity on BChE (3.97 µM) and a significant selectivity index against AChE (SI: 0.04). Kinetic studies were carried out for compounds with greater inhibitory activity of cholinesterases. Structure-activity relationships of the molecular hybrids were analyzed, through computational models using a molecular cross-docking algorithm and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy approach, which indicated a good correlation between the experimental inhibition values and the predicted free binding energy.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Isoxazóis/química , Quinolinas/química , Acetilcolinesterase/química , Sítios de Ligação , Domínio Catalítico , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Ativação Enzimática/efeitos dos fármacos , Humanos , Ligação de Hidrogênio , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
18.
Biomolecules ; 9(12)2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842463

RESUMO

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman's spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80-90 nM) AChE and moderate (IC50 5-0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure-activity relationships were discussed. The compounds inhibited also in vitro self-induced Aß(1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.


Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzimidazóis/síntese química , Benzimidazóis/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Cavalos , Humanos , Cinética , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Picratos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Pharmacol Rep ; 71(6): 1253-1263, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31675671

RESUMO

BACKGROUND: The pyridazinone nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh). Inhibition of cholinesterases is an effective method to curb Alzheimer's disease. Here, we prepared 12 new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives and evaluated their inhibitory effects on AChE/BChE in pursuit of potent dual inhibitors for Alzheirmer's Disease. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. METHOD: We obtained our compounds by the reaction of various substituted/nonsubstituted benzenesulfonic acid derivatives with 6-substitutedphenyl-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. Molecular docking studies were done using Glide and the results were evaluated on Maestro (Schrödinger, LLC, New York, NY, 2019). RESULTS: The title compounds showed moderate inhibition at 100 µg/ml against both enzymes, yet with better activity against BChE. Compound VI2a emerged as a dual inhibitor with 25.02% and 51.70% inhibition against AChE and BChE, respectively. CONCLUSION: This study supports that novel pyridazinone derivates may be used for the development of new BChE inhibitory agents. It was less potent than the reference drugs, yet promising for further modifications as a lead. The ability of the compounds to adopt energetically more favourable conformations and to engage in more key interactions in the ECBChE active gorge explains their better activity profile against ECBChE.


Assuntos
Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Humanos , Simulação de Acoplamento Molecular/métodos , Relação Estrutura-Atividade
20.
Drug Des Devel Ther ; 13: 3485-3495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631973

RESUMO

Background: In this study, 2 symmetrical and 3 unsymmetrical thioureas were synthesized to evaluate their antioxidant, antibacterial, antidiabetic, and anticholinesterase potentials. Methods: The symmetrical thioureas were synthesized in aqueous media in the presence of sunlight, using amines and CS2 as starting material. The unsymmetrical thioureas were synthesized using amines as a nucleophile to attack the phenyl isothiocyanate (electrophile). The structures of synthesized compounds were confirmed through H1 NMR. The antioxidant potential was determined using DPPH and ABTS assays. The inhibition of glucose-6-phosphatase, alpha amylase, and alpha glucosidase by synthesized compounds was used as an indication of antidiabetic potential. Anticholinesterase potential was determined from the inhibition of acetylcholinesterase and butyrylcholinesterase by the synthesized compounds. Results: The highest inhibition of glucose-6-phosphatase was shown by compound V (03.12 mg of phosphate released). Alpha amylase was most potently inhibited by compound IV with IC50 value of 62 µg/mL while alpha glucosidase by compound III with IC50 value of 75 µg/mL. The enzymes, acetylcholinesterase, and butyrylcholinesterase were potently inhibited by compound III with IC50 of 63 µg/mL and 80 µg/mL respectively. Against DPPH free radical, compound IV was more potent (IC50 = 64 µg/mL) while ABTS was more potently scavenged by compound I with IC50 of 66 µg/mL. The antibacterial spectrum of synthesized compounds was determined against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Agrobacterium tumefaction and Proteus vulgaris). Compound I and compound II showed maximum activity against A. tumefaction with MIC values of 4.02 and 4.04 µg/mL respectively. Against P. vulgaris, compound V was more active (MIC = 8.94 µg/mL) while against S. aureus, compound IV was more potent with MIC of 4.03 µg/mL. Conclusion: From the results, it was concluded that these compounds could be used as antibacterial, antioxidant, and antidiabetic agents. However, further in vivo studies are needed to determine the toxicological effect of these compounds in living bodies. The compounds also have potential to treat neurodegenerative diseases.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Tioureia/farmacologia , Acetilcolinesterase/metabolismo , Agrobacterium/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Picratos/antagonistas & inibidores , Proteus vulgaris/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Ácidos Sulfônicos/antagonistas & inibidores , Tioureia/síntese química , Tioureia/química
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