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1.
Arch Pharm (Weinheim) ; 357(2): e2300404, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38010470

RESUMO

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta , Harmina/farmacologia , Harmina/uso terapêutico , Proteínas tau/metabolismo , Proteínas tau/uso terapêutico , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Fosforilação
2.
J Med Chem ; 67(15): 12571-12600, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39041662

RESUMO

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.


Assuntos
Doença de Alzheimer , Quinases Dyrk , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Proteínas tau , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inibidores , Relação Estrutura-Atividade , Administração Oral , Masculino , Ratos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Células HEK293 , Camundongos , Descoberta de Drogas , Fosforilação/efeitos dos fármacos , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley
3.
Eur J Med Chem ; 242: 114689, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36007469

RESUMO

Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been utilized to develop innovative anti-neurodegenerative properties and is a desirable starting point for the construction of MTDLs. Herein, we explored and synthesized a series of novel coumarin derivatives and assessed their inhibitory effects on cholinesterase (AChE, BuChE), GSK-3ß, and BACE1. Among these compounds, compound 30 displayed the multifunctional profile of targeting the AChE (IC50 = 1.313 ± 0.099 µM) with a good selectivity over BuChE (SI = 24.623), GSK-3ß (19.30% inhibition at 20 µM), BACE1 (IC50 = 1.227 ± 0.112 µM), along with moderate HepG2 cytotoxicity, SH-SY5Y cytotoxicity, low HL-7702 cytotoxicity, as well as good blood-brain barrier (BBB) permeability. Kinetic and docking studies indicated that compound 30 was a competitive AChE inhibitor. Furthermore, acute toxicity experiments revealed that it was non-toxic at a dosage of 1000 mg/kg. The ADME prediction results indicate that 30 has acceptable physicochemical properties. Collectively, these findings demonstrated that compound 30 would be a potential multifunctional candidate for AD therapy.


Assuntos
Doença de Alzheimer , Neuroblastoma , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Cumarínicos/química , Desenho de Fármacos , Glicogênio Sintase Quinase 3 beta , Humanos , Ligantes , Neuroblastoma/tratamento farmacológico , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 242: 114701, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36054949

RESUMO

CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 µM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 µM, CDK9: IC50 = 0.002 µM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 µM) and butyrylcholinesterase (BuChE, IC50 = 2.768 µM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.


Assuntos
Inibidores Enzimáticos/farmacologia , Neoplasias , Tacrina , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Quinase 2 Dependente de Ciclina/metabolismo , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases , Relação Estrutura-Atividade , Tacrina/farmacologia
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