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1.
Chem Commun (Camb) ; 56(8): 1219-1222, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31895373

RESUMO

To monitor delicate changes of biological HOCl in vivo, a new probe (OH-substituted coumarin-hemicyanine, probe 2) was synthesized for NIR and ratiometric HOCl detection. Selectivity studies indicated that the electron-donating group (OH) substituted on the indolium moiety enhanced the selectivity to detect HOCl. With HOCl, the probe showed a ratiometric fluorescence (I500/I650) with a low detection limit (49.1 nM) and a rapid response (within 2 min). In addition, probe 2 was successfully applied to visualize exogenous and endogenous HOCl in living cells and animals and exhibited a perfect mitochondria target ability. This probe has been further studied as a potential and powerful tool to probe HOCl in arthritis models.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Indóis/química , Animais , Artrite/induzido quimicamente , Artrite/diagnóstico , Carragenina , Cumarínicos/síntese química , Cumarínicos/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Indóis/síntese química , Indóis/toxicidade , Limite de Detecção , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Mitocôndrias/metabolismo , Células RAW 264.7 , Espectrometria de Fluorescência/métodos , Peixe-Zebra
2.
Bioorg Chem ; 94: 103413, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31791679

RESUMO

A series of new ferulic acid derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer's disease. In vitro studies indicated that most compounds showed significant potency to inhibit self-induced ß-amyloid (Aß) aggregation and acetylcholinesterase (AChE), and had good antioxidant activity. Specifically, compound 4g exhibited the potent ability to inhibit cholinesterase (ChE) (IC50, 19.7 nM for hAChE and 0.66 µM for hBuChE) and the good Aß aggregation inhibition (49.2% at 20 µM), and it was also a good antioxidant (1.26 trolox equivalents). Kinetic and molecular modeling studies showed that compound 4g was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, compound 4g could remarkably increase PC12 cells viability in hydrogen peroxide-induced oxidative cell damage and Aß-induced cell damage. Finally, compound 4g had good ability to cross the BBB using the PAMPA-BBB assay. These results suggested that compound 4g was a promising multifunctional ChE inhibitor for the further investigation.

3.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694349

RESUMO

Based upon the intramolecular charge transfer (ICT) mechanism, a novel ratiometric fluorescent probe EB was developed to detect SO32-/HSO3-. The probe displayed both colorimetric and ratiometric responses toward SO32-/HSO3-. It displayed a quick response (within 60 s), good selectivity and high sensitivity (a detection limit of 28 nM) towards SO32-/HSO3-. The SO32-/HSO3- sensing mechanism was confirmed as the Michael addition reaction by ESI-MS. Moreover, the probe could be applied to measure the level of sulfite in real samples, like sugar and chrysanthemum, and it could also be used to detect SO32-/HSO3- in HepG2 cells through confocal fluorescence microscopy, which proved its practical application in clinical diagnosis.

4.
Analyst ; 144(11): 3676-3684, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31086902

RESUMO

Biothiols, including cysteine (Cys), homocysteine (Hcy), glutathione (GSH) and H2S, play important roles in human physiological processes. However, it is a great difficulty to distinguish biothiols from each other because of their similar chemical properties. Based on Nile red, we have designed and synthesized a near-infrared fluorescent probe for discriminating Cys/Hcy from GSH/H2S by a dual-channel detection method. Using an ether bond, near-infrared Nile red was attached to 7-nitrobenzofurazan to construct the probe. Due to the photo-induced electron transfer, the probe showed almost no fluorescence from the green to red emission band. But upon the addition of Cys (0-150 µM) or Hcy (0-200 µM), the probe exhibited a noteworthy fluorescence "turn-on" signal in two unique emission bands (Green and Red) with a fast response (within 30 min). In contrast, the probe displayed an increase in fluorescence only in the red channel when encountering GSH (0-70 µM) or H2S (0-50 µM), and GSH/H2S could be tested respectively by different response time. The limit of detection was calculated to be 0.09 µM (Cys), 0.30 µM (Hcy), 0.24 µM (GSH), and 0.04 µM (H2S), respectively (based on S/N = 3). The desirable dual-channel detection could be achieved in serum samples and living cells. Moreover, the probe could be applied for bioimaging in mice, which indicated its potential application in the clinic.


Assuntos
Cisteína/análise , Corantes Fluorescentes/química , Glutationa/análise , Homocisteína/análise , Sulfeto de Hidrogênio/análise , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/síntese química , 4-Cloro-7-nitrobenzofurazano/toxicidade , Animais , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Camundongos Nus , Imagem Óptica/métodos , Oxazinas/síntese química , Oxazinas/química , Oxazinas/toxicidade , Espectrometria de Fluorescência
5.
Bioorg Chem ; 81: 512-528, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30245233

RESUMO

A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 µM and 0.0089 µM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Tiocarbamatos/química , Tiocarbamatos/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Linhagem Celular , Inibidores da Colinesterase/toxicidade , Cumarínicos/toxicidade , Desenho de Drogas , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/toxicidade , Tiocarbamatos/toxicidade
6.
Molecules ; 23(9)2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30150543

RESUMO

A series of novel alkyl amine-substituted icariside II (ICA II) derivatives were synthesized by Mannich reactions at the 6-C position (compounds 4a⁻d) and changing the carbon chain length at the 7-OH position (compounds 7a⁻h), and their in vitro antitumor activity towards human breast cancer lines (MCF-7 and MDA-MB-231) and human hepatoma cell lines (HepG2 and HCCLM3-LUC) were evaluated by the MTT assay. Compared with ICA II, most of the twelve derivatives showed good micromole level activity and a preliminary structure-activity relationship (SAR) for the anticancer activity was obtained. Compound 7g showed the most potent inhibitory activity for the four cancer cell lines (13.28 µM for HCCLM3-LUC, 3.96 µM for HepG2, 2.44 µM for MCF-7 and 4.21 µM for MDA-MB-231), which was 2.94, 5.54, 12.56 and 7.72-fold stronger than that of ICA II. The preliminary SAR showed that the introduction of a alkyl amine substituent at 6-C was not favorable for the anticancer activity, while most of the 7-O-alkylamino derivatives exhibited good antitumor activity and the anticancer activity 7-O-alkylamino derivatives were influenced by the alkyl chain length and the different terminal amine substituents. Furthermore, the effects of compound 7g on apoptosis and cell cycle of MCF-7 cells were further investigated, which showed that compound 7g triggered apoptosis and arrested the cell cycle at the G0/G1 phase in MCF-7 cells. Our findings indicate that compound 7g may be a promising anticancer drug candidate lead.


Assuntos
Aminas , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Aminas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Flavonoides/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade
7.
Bioorg Chem ; 76: 130-139, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29172101

RESUMO

Novel hybrids with MAO and Aß (1-42) self-aggregation inhibitory activities were designed and synthesized with the employment of indazole moiety and resveratrol. The biological screening results indicated that most compounds displayed potent inhibitory activity for Aß (1-42) self-aggregation, and obvious selective inhibition to MAO-B. Among these compounds, compound 6e was the most potent inhibitor not only for hMAO-B (IC50 = 1.14 µM) but also for Aß (1-42) self-aggregation (58.9% at 20 µM). Molecular modeling and kinetic studies revealed that compound 6e was a competitive MAO-B inhibitor, which can occupy the active site of MAO-B, and interact with Aß (1-42) via π-π and cation-π stacking interactions. In addition, compound 6e had no toxicity on PC12 cells and could cross the BBB. Collectively, all these results suggested that compound 6e might be a promising multi-target lead compound worthy of further investigation.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Desenho de Drogas , Indazóis/química , Inibidores da Monoaminoxidase/química , Fragmentos de Peptídeos/antagonistas & inibidores , Multimerização Proteica/efeitos dos fármacos , Resveratrol/análogos & derivados , Animais , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Indanos/farmacologia , Indazóis/síntese química , Indazóis/toxicidade , Iproniazida/farmacologia , Cinética , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/toxicidade , Ratos , Resveratrol/síntese química , Resveratrol/toxicidade
8.
Molecules ; 22(10)2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28954423

RESUMO

A new coumarin-based fluorescent probe, containing an allylic esters group, has been designed and synthesized for sensing cysteine in physiological pH. In this fluorescent probe, the coumarin was applied as the fluorophore and an allylic esters group was combined as both a fluorescence quencher and a recognition unit. The probe can selectively and sensitively detect cysteine (Cys) over homocysteine, glutathione, and other amino acids, and has a rapid response time of 30 min and a low detection limit of 47.7 nM. In addition, the probe could be applied for cell imaging with low cytotoxicity.


Assuntos
Cumarínicos , Cisteína , Corantes Fluorescentes , Imagem Molecular/métodos , Linhagem Celular , Cumarínicos/química , Cisteína/química , Cisteína/metabolismo , Corantes Fluorescentes/química , Humanos , Concentração de Íons de Hidrogênio , Microscopia de Fluorescência , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta
9.
Eur J Med Chem ; 139: 48-59, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-28797883

RESUMO

Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aß (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 µM for eeAChE; 2.32 µM for eqBuChE; 1.57 µM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aß (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Compostos de Piridínio/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Inibidores da Colinesterase/química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Agregados Proteicos/efeitos dos fármacos , Compostos de Piridínio/química , Ratos , Relação Estrutura-Atividade
10.
J Enzyme Inhib Med Chem ; 32(1): 776-788, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28585866

RESUMO

A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aß (1-42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC50, 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 µM for eqBuChE and 4.4 µM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Aß (1-42) aggregation (64.7% at 20 µM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer's diseases.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Cinamatos/farmacologia , Desenho de Drogas , Compostos de Piridínio/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Compostos de Piridínio/química , Ratos , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 133: 184-196, 2017 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-28388521

RESUMO

A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced ß-amyloid (Aß) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of Aß aggregation (53.7% at 20 µM) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and Aß (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment.


Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Indanos/química , Indanos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Piperidinas/química , Piperidinas/farmacologia , Agregados Proteicos/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/ultraestrutura , Animais , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular , Inibidores da Colinesterase/farmacocinética , Donepezila , Desenho de Drogas , Electrophorus , Humanos , Indanos/farmacocinética , Camundongos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/ultraestrutura , Piperidinas/farmacocinética , Compostos de Piridínio/química , Compostos de Piridínio/farmacocinética , Compostos de Piridínio/farmacologia , Ratos , Relação Estrutura-Atividade
12.
Medchemcomm ; 8(2): 471-478, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108765

RESUMO

A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC50 = 0.35 µM) and 10e (IC50 = 0.19 µM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.

13.
J Enzyme Inhib Med Chem ; 31(sup3): 41-53, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27384289

RESUMO

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of donepezil-like compounds were designed, synthesized and evaluated. In vitro studies showed that most of the designed compounds displayed potent inhibitory activities toward AChE, BuChE, MAO-B and MAO-A. Among them, w18 was a promising agent with balanced activities, which exhibited a moderate cholinesterase inhibition (IC50, 0.220 µM for eeAChE; 1.23 µM for eqBuChE; 0.454 µM for hAChE) and an acceptable inhibitory activity against monoamine oxidases (IC50, 3.14 µM for MAO-B; 13.4 µM for MAO-A). Moreover, w18 could also be a metal-chelator, and able to cross the blood-brain barrier with low cell toxicity on PC12 cells. Taken together, these results suggested that w18 might be a promising multitargeted compound for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Indanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Sobrevivência Celular , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Indanos/síntese química , Indanos/química , Cinética , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Piperidinas/síntese química , Piperidinas/química , Ratos , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 24(7): 1528-39, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26917219

RESUMO

Combining N-benzylpiperidine moiety of donepezil and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activity were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for AChE and BuChE, and clearly selective inhibition to MAO-B. Of these compounds, 5m was the most potent inhibitor for eeAChE and eqBuChE (0.87 µM and 0.93 µM, respectively), and it was also a good and balanced inhibitor to hChEs and hMAO-B (1.37 µM for hAChE; 1.98 µM for hBuChE; 2.62 µM for hMAO-B). Molecular modeling and kinetic studies revealed that 5m was a mixed-type inhibitor, which bond simultaneously to CAS, PAS and mid-gorge site of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, 5m showed good ability to cross the BBB and had no toxicity on SH-SY5Y neuroblastoma cells. Collectively, all these results suggested that 5m might be a promising multi-target lead candidate worthy of further pursuit.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Desenho de Drogas , Indanos/farmacologia , Piperidinas/farmacologia , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Cumarínicos/química , Donepezila , Relação Dose-Resposta a Droga , Enguias , Humanos , Indanos/química , Modelos Moleculares , Estrutura Molecular , Terapia de Alvo Molecular , Piperidinas/química , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 95: 153-65, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25812965

RESUMO

A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 µM). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Benzopiranos/farmacologia , Inibidores da Colinesterase/farmacologia , Cumarínicos/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/química , Piperazinas/farmacologia , Tacrina/química , Barreira Hematoencefálica , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Sobrevivência Celular , Células Cultivadas , Desenho de Drogas , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Humanos , Cinética , Modelos Moleculares , Simulação de Acoplamento Molecular , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Neuroblastoma/patologia
16.
Eur J Med Chem ; 93: 42-50, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25656088

RESUMO

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/síntese química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Inibidores da Colinesterase/síntese química , Cromanos/farmacologia , Fármacos Neuroprotetores/síntese química , Tacrina/farmacologia , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/efeitos adversos , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/farmacologia , Cromanos/efeitos adversos , Cromanos/química , Cromanos/farmacocinética , Desenho de Drogas , Técnicas In Vitro , Cinética , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Células PC12 , Picratos/química , Ratos , Suínos , Tacrina/efeitos adversos , Tacrina/química , Tacrina/farmacocinética
17.
Bioorg Med Chem Lett ; 25(3): 508-13, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25542589

RESUMO

A series of coumarin derivatives were designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most of these compounds exhibited significant potency to inhibit hMAO-B selectively and self-induced Aß1-42 aggregation. In particular, compound 13 presented the greatest potential to inhibit hMAO-B (IC50=0.081µM, SI >1234) and good inhibition of Aß1-42 aggregation (52.9% at 20µM). Moreover, compound 13 could function as a metal-chelator, penetrate the blood-brain barrier (BBB) and show low cell toxicity in rat pheochromocytoma (PC12) and SH-SY5Y cells. Taken together, these results suggested that compound 13 might be a promising multifunctional agent for AD treatment.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Quelantes/química , Cumarínicos/química , Inibidores da Monoaminoxidase/química , Monoaminoxidase/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/uso terapêutico , Quelantes/toxicidade , Cumarínicos/uso terapêutico , Cumarínicos/toxicidade , Desenho de Drogas , Humanos , Metais/química , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/uso terapêutico , Inibidores da Monoaminoxidase/toxicidade , Células PC12 , Estrutura Terciária de Proteína , Ratos
18.
Bioorg Med Chem ; 22(21): 6089-104, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25282654

RESUMO

A series of tacrine-(ß-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced ß-amyloid (Aß) aggregation, Cu(2+)-induced Aß (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aß aggregation (65.8% at 20 µM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Carbolinas/química , Carbolinas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Tacrina/química , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Carbolinas/farmacocinética , Linhagem Celular , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Inibidores da Colinesterase/farmacocinética , Desenho de Drogas , Electrophorus , Cavalos , Humanos , Simulação de Acoplamento Molecular , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Tacrina/farmacocinética
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