Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Biomol Struct Dyn ; 41(10): 4696-4710, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35532095

RESUMO

Targeting kinases with oncogenic driver mutations in malignancies with allosteric kinase inhibitors is a promising new treatment technique. EGFR inhibitors targeting the L858R/T790M/C797S mutation bearing thiazolidine-4-one scaffold were discovered, optimized, synthesized, and biologically evaluated. According to in silico and in vitro studies, compounds 6a and 6b resulted to be highly potent with IC50 values of 120 nM and 134 nM and good selectivity. Compound 6a displayed significant antioxidant activity, with a DPPH radical scavenging value of 92.15%. The potency of compounds was also compared with ADMET and molecular dynamics simulations study. A comparative simulation of model protein and protein-ligand complex in presence and absence of compound 6a has been carried out.Communicated by Ramaswamy H. Sarma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Simulação de Dinâmica Molecular , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/química , Mutação
2.
Bioorg Chem ; 115: 105226, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364055

RESUMO

Two different schemes of novel substituted quinoline derivatives were designed and synthesized via simple reaction steps and conditions. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. Free energy perturbations were carried out to determine the absolute binding free energy of a protein-ligand complex in the form of ΔGbinding, which in turn provided 4ab and 5ad as the most potential contenders through the structural enhancement in the determined initial scaffolds. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Compound 4ad (6-chloro-2-(isoindolin-2-yl)-4-methylquinoline) has shown excellent inhibitory activities against mutant EGFR kinase with IC50 value 0.91 µM. The potency of compounds 4ab, 4ad and 5adwas compared throughan insilicoADMET study.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Termodinâmica
3.
Bioorg Med Chem Lett ; 40: 127916, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33689875

RESUMO

A library of novel flavonoid derivatives with diverse heterocyclic groups was designed and efficiently synthesized. Structures of the newly synthesized compounds 4a-i and 8a-l have been characterized by 1H NMR, 13C NMR, MS and elemental analysis. Anticancer activities were evaluated against MCF-7, A549, HepG2 and MCF-10A by MTT based assay. Compared with the positive control Adriamycin, compounds 4a, 4b, 4c, 4d, 8d, 8e and 8j were found to be most active anti-proliferative compounds against human cancer cell line. We found that compounds 4a and 4c exhibited inhibition of enzyme topoisomerase II with IC50 values 10.28 and 12.38 µM, respectively. In silico docking study of synthesized compounds showed that compounds 4a and 4c have good binding affinity toward topoisomerase IIα enzyme and have placed in between DNA base pair at active site of enzyme. In silico ADME prediction results that flavonoid coumarin analogues 4a-i could be exploited as an oral drug candidate.


Assuntos
Antineoplásicos/síntese química , DNA Topoisomerases Tipo II/metabolismo , Flavonoides/síntese química , Inibidores da Topoisomerase II/síntese química , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/química , Simulação por Computador , Cumarínicos/química , Clivagem do DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/farmacologia , Flavonoides/farmacologia , Humanos , Imidazóis/química , Ligação Proteica , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacologia
4.
Bioorg Chem ; 107: 104612, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33476869

RESUMO

New substituted quinoline derivatives were designed and synthesized via a five-step modified Suzuki coupling reaction. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. All docking studies confirmed high potency and flexibility towards wild type as well as a mutated enzyme. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M/C797S and L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Most of the quinoline derivatives revealed a significant cytotoxic effect. The IC50 values of 4-(4-methylquinolin-2-yl)phenyl 4-(chloromethyl)benzoate (5j) were found to be 0.0042 µM, 0.02 µM, 1.91 µM, 3.82 µM and 3.67 µM while IC50 values of osimertinib were 0.0040 µM, 0.02 µM, ND, 0.99 µM and 1.22 µM, respectively. Compound 5j has shownexcellent inhibitory activities against EGFR kinases triple mutant with IC 50 value 1.91 µM. It was observed that, compared to H1975, A549 and A431 cell lines, synthesized compounds significantly inhibited proliferation of the HCC827 cell line. These data suggested that synthesized compounds showed promising selective anticancer activity against tumor cells harboring EGFR Del E746-A750. The potency of compound 5j was compared through molecular dynamic simulations andan insilicoADMET study. QSAR models were generated and the best model was correctly compared with respect to predicted and observed activity of compounds. The built model will assist to design, refine and construct novel substituted quinoline derivatives as potent EGFR inhibitors in near future.


Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinolinas/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Meia-Vida , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Quinolinas/metabolismo , Quinolinas/farmacologia
5.
J Biomol Struct Dyn ; 39(15): 5376-5398, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32608331

RESUMO

The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. EGFR inhibitors binding allosterically to C797S mutant EGFR enzyme have been developed. Here, database building, library screening performing R-group enumeration and scaffold hopping technique for increasing the EGFR binding affinity of compounds have been carried out. Virtual screening was performed subjecting to HTVS, SP and XP docking protocol along with its relative binding free energy calculations. Molecular docking studies provided the information about binding pockets and interactions of molecules on mutant (PDB: 5D41) as well as wild type (PDB: 4I23) EGFR enzyme. This was supported with ADMET and molecular simulation studies. On the basis of glide score and protein-ligand interactions, highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. The virtually screened molecules can act as potential EGFR inhibitors in the management of drug resistance. Communicated by Ramaswamy H. Sarma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteínas Quinases/farmacologia
6.
Bioorg Med Chem Lett ; 30(22): 127592, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33010448

RESUMO

In search of new active molecules against MCF-7, A549 and HepG2, tetrazole based pyrazoline and isoxazoline derivatives under both conventional and ultrasonic irradiation method were designed and efficiently synthesized. Structures of newly synthesized compounds 5a-h and 6a-h were characterized by 1H NMR, 13C NMR, MS and elemental analysis. Several derivatives were found to be excellent cytotoxic against MCF-7, A549 and HepG2 cell lines characterized by lower IC50 values (0.78-3.12 µg/mL). Compounds 5b and 5c demonstrated an antiproliferative effect comparable to that of CA-4. Western blot analysis revealed that, reported compounds accumulate more tubulin in the soluble fraction. Docking studies suggested that, binding of these compounds mimics at the colchicine site of tubulin. In vitro study revealed that the tetrazole based pyrazolines and isoxazolines may possess ideal structural requirements for further development of novel therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Isoxazóis/farmacologia , Pirazóis/farmacologia , Tetrazóis/farmacologia , Tubulina (Proteína)/metabolismo , Ondas Ultrassônicas , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Estrutura Molecular , Polimerização/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tetrazóis/química
7.
Molecules ; 25(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244772

RESUMO

Metabolism is one of the prime reasons where most of drugs fail to accomplish their clinical trials. The enzyme CYP3A4, which belongs to the superfamily of cytochrome P450 enzymes (CYP), helps in the metabolism of a large number of drugs in the body. The enzyme CYP3A4 catalyzes oxidative chemical processes and shows a very broad range of ligand specificity. The understanding of the compound's structure where oxidation would take place is crucial for the successful modification of molecules to avoid unwanted metabolism and to increase its bioavailability. For this reason, it is required to know the site of metabolism (SOM) of the compounds, where compounds undergo enzymatic oxidation. It can be identified by predicting the accessibility of the substrate's atom toward oxygenated Fe atom of heme in a CYP protein. The CYP3A4 enzyme is highly flexible and can take significantly different conformations depending on the ligand with which it is being bound. To predict the accessibility of substrate atoms to the heme iron, conventional protein-rigid docking methods failed due to the high flexibility of the CYP3A4 protein. Herein, we demonstrated and compared the ability of the Glide extra precision (XP) and Induced Fit docking (IFD) tool of Schrodinger software suite to reproduce the binding mode of co-crystallized ligands into six X-ray crystallographic structures. We extend our studies toward the prediction of SOM for compounds whose experimental SOM is reported but the ligand-enzyme complex crystal structure is not available in the Protein Data Bank (PDB). The quality and accuracy of Glide XP and IFD was determined by calculating RMSD of docked ligands over the corresponding co-crystallized bound ligand and by measuring the distance between the SOM of the ligand and Fe atom of heme. It was observed that IFD reproduces the exact binding mode of available co-crystallized structures and correctly predicted the SOM of experimentally reported compounds. Our approach using IFD with multiple conformer structures of CYP3A4 will be one of the effective methods for SOM prediction.


Assuntos
Citocromo P-450 CYP3A/química , Descoberta de Drogas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Sítios de Ligação , Citocromo P-450 CYP3A/metabolismo , Humanos , Conformação Molecular , Ligação Proteica , Relação Estrutura-Atividade
8.
Molecules ; 23(2)2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29462951

RESUMO

Herein, we report an environmentally friendly, rapid, and convenient ionic liquid ([Et3NH][HSO4])-promoted facile synthesis of ethyl 4-(6-substituted-4-oxo-4H-chromen-3-yl)-6-methyl-2-thioxo/oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 4(a-f) and 4-(6-substituted-4-oxo-4H-chromen-3-yl)-6-methyl-2-thioxo/oxo-1,2,3,4-tetrahydropyrimidine-5- carbohydrazide derivatives 6(a-f). All the synthesized derivatives 4(a-f) and 6(a-f) were evaluated for their in vitro antifungal and antibacterial activity, by method recommended by National Committee for Clinical Laboratory Standards (NCCLS). The compound 6c bearing a fluoro group on the chromone ring and oxygen and a hydrazino group (-NHNH2) on the pyrimidine ring, was found to be the most potent antibacterial compound amongst the synthesized derivatives. The compound 6f bearing a methoxy group (-OCH3) on the chromone ring and sulphur group on the pyrimidine ring, was found to exhibit equipotent antifungal activity when compared with the standard drug miconazole. A D-alanine-D-alanine ligase (DdlB) enzyme assay study and an ergosterol extraction and quantitation assay study were performed to predict the mode of action of the synthesized compounds. A molecular docking study was performed to predict the binding interactions with receptors and mode of action of the synthesized derivatives. Further, analysis of the ADMET parameters for the synthesized compounds has shown that these compounds have good oral drug-like properties and can be developed as oral drug candidates. To establish the antimicrobial selectivity and safety, the most active compounds 6c and 6f were further tested for cytotoxicity against the human cancer cell line HeLa and were found to be non-cytotoxic in nature. An in vivo acute oral toxicity study was also performed for the most active compounds 6c and 6f and the results indicated that the compounds are non-toxic in nature.


Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Cromonas/síntese química , Pirimidinas/síntese química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Cromonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Líquidos Iônicos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade
9.
Artigo em Inglês | MEDLINE | ID: mdl-29141568

RESUMO

BACKGROUND: Due to the need and adverse effects associated with the available anti-inflammatory agents, an attempt was made to develop the new anti-inflammatory agents with better activity and lesser adverse effects. OBJECTIVE: Synthetic approaches based on chemical modification of NSAIDs have been undertaken with the aim of improving NSAIDs safety profile. METHOD: In the present study, a series of thiazole derivatives (3a-3x) was synthesized and tested for its anti-inflammatory with analgesic and nitric oxide releasing properties. In this work, synthesis of molecules containing substituted diaryl ring on 5-membered thiazole ring with nitric oxide releasing moiety is described. RESULTS: Out of the twenty four synthesized compounds, five compounds showed considerable anti-inflammatory and analgesic activity in comparison with the standard. Most of the synthesized compounds showed considerable nitric oxide-releasing property. The molecular docking study was used to rationalize binding interaction at the active site and the result showed good binding interaction. CONCLUSION: From the results of pharmacological studies, we conclude that the synthesized compounds have not only retained, but showed enhanced anti-inflammatory and analgesic profile.


Assuntos
Acetatos/química , Analgésicos/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios/química , Química Farmacêutica/métodos , Edema/tratamento farmacológico , Tiazóis/química , Acetatos/uso terapêutico , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Carragenina , Edema/induzido quimicamente , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazóis/uso terapêutico
10.
Molecules ; 22(7)2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28703783

RESUMO

The work reports the synthesis under solvent-free condition using the ionic liquid [Et3NH][HSO4] as a catalyst of fifteen novel 3-((dicyclohexylamino)(substituted phenyl/heteryl)-methyl)-4-hydroxy-2H-chromen-2-onederivatives 4a-o as potential antimicrobial agents. The structures of the synthesized compounds were confirmed by IR, ¹H-NMR, 13C-NMR, mass spectral studies and elemental analyses. All the synthesized compounds were evaluated for their in vitro antifungal and antibacterial activity. The compound 4k bearing 4-hydroxy-3-ethoxy group on the phenyl ring was found to be the most active antifungal agent. The compound 4e bearing a 2,4-difluoro group on the phenyl ring was found to be the most active antibacterial agent. The mode of action of the most promising antifungal compound 4k was established by an ergosterol extraction and quantitation assay. From the assay it was found that 4k acts by inhibition of ergosterol biosynthesis in C. albicans. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds to the active site of lanosterol 14α-demethylase, which suggests that the tested compounds inhibit the synthesis of this enzyme. The synthesized compounds were analyzed for in silico ADMET properties to establish oral drug like behavior and showed satisfactory results. To establish the antimicrobial selectivity and safety, the most active compounds 4e and 4k were further tested for cytotoxicity against human cancer cell line HeLa and were found to be non-cytotoxic in nature. An in vivo acute oral toxicity study was also performed for the most active compounds 4e and 4k and results indicated that the compounds are non-toxic.


Assuntos
Antibacterianos/síntese química , Anti-Infecciosos/síntese química , Cumarínicos/síntese química , Antibacterianos/química , Antibacterianos/uso terapêutico , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Cumarínicos/química , Cumarínicos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 26(15): 3525-8, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27324976

RESUMO

A series of novel molecules containing thiazole ring structure were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by (1)H NMR, (13)C NMR, Mass spectrum and the purity was checked through HPLC analysis. Among these synthesized compounds, 3a-3i and 6a-6c were tested for their antimicrobial activity (minimum inhibitory concentration) against a series of strains of Bacillus subtilis, Staphylococcus aureus and Escherichia coli for antibacterial activity and against the strains of Candida albicans, Aspergillus flavus and Aspergillus niger for antifungal activity respectively. The results of the antimicrobial screening data revealed that most of the tested compounds showed moderate to good microbial inhibitions.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Ácidos Carboxílicos/farmacologia , Tiazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus flavus/efeitos dos fármacos , Aspergillus niger/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...