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1.
Curr Top Med Chem ; 21(22): 1999-2017, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225623

RESUMO

BACKGROUND: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. OBJECTIVE: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. METHODS: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. RESULTS: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). CONCLUSION: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.


Assuntos
Flavonoides/síntese química , Flavonoides/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia
2.
Curr Top Med Chem ; 20(2): 153-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31648640

RESUMO

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3ß isoforms is likely to represent an effective strategy against AD. OBJECTIVE: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3ß kinase inhibitors. METHODS: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3ß activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3ß complex [Protein Data Bank (PDB) code: 1Q3D]. RESULTS: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3ß inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3ß enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. CONCLUSION: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3ß inhibitors.


Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Cumarínicos/química , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
3.
J Biomol Struct Dyn ; 28(5): 787-96, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21294589

RESUMO

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.


Assuntos
Química Farmacêutica , Desenho Assistido por Computador , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/química , Sítios de Ligação , Bases de Dados Factuais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Humanos , Hipoglicemiantes/uso terapêutico , Ligantes , Conformação Molecular , Simulação de Dinâmica Molecular
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