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

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Bioorg Chem ; 147: 107372, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38653152

RESUMO

Joining the global demand for the discovery of potent NSAIDs with minimized ulcerogenic effect, new pyrazole clubbed thiazole derivatives 5a-o were designed and synthesized. The new derivatives were initially evaluated for their analgesic activity. Eight compounds 5a, 5c, 5d, 5e, 5f, 5h, 5m, and 5o showed higher activity than Indomethacin (potency = 105-130 % vs. 100 %). Subsequently, they were picked for further evaluation of their anti-inflammatory activity, ulcerogenic liability as well as toxicological studies. Derivatives 5h and 5m showed a potential % edema inhibition after 3 h (79.39 % and 72.12 %, respectively), with a promising safety profile and low ulcer indices (3.80 and 3.20, respectively). The two compounds 5h and 5m were subjected to in vitro COX-1 and COX-2 inhibition assay. The candidate 5h showed nearly equipotent COX-1 inhibition (IC50 = 38.76 nM) compared to the non-selective reference drug Indomethacin (IC50 = 35.72 nM). Compound 5m expressed significant inhibitory activities and a higher COX-2 selectivity index (IC50 = 87.74 nM, SI = 2.05) in comparison with Indomethacin (SI = 0.52), with less selectivity than Celecoxib (SI = 8.31). Simulation docking studies were carried out to gain insights into the binding interaction of compounds 5h and 5m in the vicinity of COX-1 and COX-2 enzymes that illustrated the importance of pyrazole clubbed thiazole core in hydrogen bonding interactions. The thiazole motif of compounds 5h and 5m exhibited a well orientation toward COX-1 Arg120 key residue by hydrogen bonding interactions. Compound 5h revealed an additional arene-cation interaction with Arg120 that could rationalize its superior COX-1 inhibitory activity. Compounds 5h and 5m overlaid the co-crystallized ligand Celecoxib I differently in the active site of COX-2. Compound 5m showed an enhanced accommodation with binding energy of - 6.13 vs. - 1.70 kcal/mol of compounds 5h. The naphthalene ring of compound 5m adopted the Celecoxib I benzene sulfonamide region that is stabilized by hydrogen-arene interactions with the hydrophobic sidechains of the key residues Ser339 and Phe504. Further, the core structure of compound 5m, pyrazole clubbed thiazole, revealed deeper hydrophobic interactions with Ala513, Leu517 and Val509 residues. Finally, a sensitive and accurate UPLC-MS/MS method was developed for the simultaneous estimation of some selected promising pyrazole derivatives in rat plasma. Accordingly, compounds 5h and 5m were suggested to be promising potent analgesic and anti-inflammatory agents with improved safety profiles and a novel COX isozyme modulation activity.


Assuntos
Analgésicos , Anti-Inflamatórios não Esteroides , Ciclo-Oxigenase 2 , Edema , Simulação de Acoplamento Molecular , Tiazóis , Animais , Masculino , Camundongos , Ratos , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/síntese química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/síntese química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Edema/tratamento farmacológico , Edema/induzido quimicamente , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química
2.
Drug Dev Res ; 85(2): e22163, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38419305

RESUMO

In the present work, five series of new 2,3-disubstituted quinazolin-4(3H)-ones 4a-c, 5a-d, 6a-g, 7a,b, and 9a-c were designed, synthesized, and screened in vitro for their cytotoxic activity against 60 cancer cell lines by the National Cancer Institute, USA. Five candidates 4c, 6a, 6b, 6d, and 6g revealed promising cytotoxicity with significant percentage growth inhibition in the range of 81.98%-96.45% against the central nervous system (CNS) (SNB-19), melanoma (MDA-MB-435), and non-small cell lung cancer (HOP-62) cell lines. The in vitro cytotoxic half maximal inhibitory concentration (IC50 ) values for the most active compounds 4c, 6a, 6b, 6d, and 6g against the most sensitive cell lines were evaluated. Additionally, screening their cyclin-dependent kinase 2 (CDK2) inhibitory activity was performed. Ortho-chloro-benzylideneamino derivative 6b emerged as the most potent compound with IC50 = 0.67 µM compared to Roscovitine (IC50 = 0.64 µM). The most active candidates arrested the cell cycle at G1, S phases, or both, leading to cell death and inducing apoptosis against CNS (SNB-19), melanoma (MDA-MB-435), and non-small cell lung cancer (HOP-62) cell lines. The molecular docking study verified the resulting outcomes for the most active candidates in the CDK2-binding pocket. Finally, physicochemical, and pharmacokinetic properties deduced that compounds 4c, 6a, 6b, 6d, and 6g displayed significant drug-likeness properties. According to the obtained results, the newly targeted compounds are regarded as promising scaffolds for the continued development of novel CDK2 inhibitors.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Humanos , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Simulação de Acoplamento Molecular , Melanoma/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Antineoplásicos/química , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinase 2 Dependente de Ciclina/metabolismo
3.
Drug Dev Res ; 85(3): e22193, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38685605

RESUMO

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 µM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.


Assuntos
Antineoplásicos , Compostos Bicíclicos Heterocíclicos com Pontes , Óxidos N-Cíclicos , Desenho de Fármacos , Indolizinas , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases , Compostos de Piridínio , Humanos , Compostos de Piridínio/farmacologia , Compostos de Piridínio/química , Indolizinas/farmacologia , Indolizinas/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Relação Estrutura-Atividade , Pirimidinas/farmacologia , Pirimidinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo
4.
Bioorg Chem ; 139: 106678, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37354661

RESUMO

Appertaining to its paracrine and autocrine signaling loops, VEGFR-2 succeeded in grabbing attention as one of the leading targets in cancer treatment. Based on the foregoing and our comprehensive studies regarding pharmacophoric features and activity of sorafenib, novel phenylpyridazinone based VEGFR-2 inhibitors 4, 6a-e, 7a,b, 9a,b, 12a-c, 13a,b, 14a,b, 15a,b, and 17a-d were optimized. An assortment of biological assays was conducted to assess the antiangiogenic and apoptotic activities of the synthesized derivatives. In vitro VEGFR-2 kinase assay verified the inhibitory activity of the synthesized derivatives with IC50 values from 49.1 to 418.0 nM relative to the reference drug sorafenib (IC50 = 81.8 nM). Antiproliferative activity against HUVECs revealed that compounds 2-{2-[2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetyl]hydrazineyl}-N-(p-tolyl)acetamide (12c) and 2-[(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-phenylpyridazin-3(2H)-one (13a) possessed superior activity (IC50 values = 11.5 and 12.3 nM, respectively) in comparison to sorafenib (IC50 = 23.2 nM). For the purpose of appraising their antiproliferative effect, derivatives 12c and 13a were exposed to cell cycle analysis, apoptotic, cell invasion and migration assays in addition to determination of VEGFR-2 in protein level. Moreover, cytotoxicity as well as selectivity index against WI-38 cell line was measured to examine safety of derivatives 12c and 13a. After that, molecular docking study was executed on the top five compounds in the in vitro VEGFR-2 kinase assay 6d, 12c, 13a, 14a and 17c to get a deep perception on binding mode of the synthesized compounds and correlate the design strategy with biological results. Finally, physicochemical, pharmacokinetic properties, and drug-likeness studies were performed on the top five derivative in in vitro VEGFR-2 kinase assay.


Assuntos
Antineoplásicos , Antineoplásicos/química , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
5.
Bioorg Chem ; 136: 106561, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37119786

RESUMO

The new series of 5a-e, 6a-e and 7a-e derivatives were designed, synthesized and tested for their anticonvulsant activity using "gold standard methods" ScPTZ and MES model, neurotoxicity, liver enzymes and neurochemical assay. Screening of the synthesized analogues exhibited variable anticonvulsant potential especially in chemically induced seizures. Quantification study showed that compounds 6d and 6e were the most potent analogues with ED50 44.77 and 11.31 mg/kg, respectively in ScPTZ test. Compound 6e (0.031 mmol/kg) was about 2 fold more potent than phenobarbital (0.056 mmol/kg) and was 30 folds more potent than Ethosuximide (0.92 mmol/kg) as reference standard drug. Moreover, all the synthesized compounds were screened for acute neurotoxicity using the rotarod method to recognize motor impairment, whereas all compounds devoid from neurotoxicity except compound 5a, 5b, 7a and 7e. The most active compounds were examined for acute toxicity and the estimates for LD50 were stated. Further neurochemical study was performed to investigate the effect of the most active compounds in ScPTZ test on GABA level in brain of the mice; a significant elevation in GABA level was obvious for compound 6d compared to control group confirming GABAergic modulating activity. Docking study was accomplished to examine the binding interaction of the newly synthesized analogues with GABA-AT enzyme. Additionally, physicochemical and pharmacokinetic parameters were predicted. The attained results indicate that the newly target compounds are considered a promising scaffolds for further development of newly anticonvulsants.


Assuntos
Anticonvulsivantes , Agonistas GABAérgicos , Animais , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/química , Desenho de Fármacos , Agonistas GABAérgicos/efeitos adversos , Ácido gama-Aminobutírico , Estrutura Molecular , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade
6.
Bioorg Chem ; 124: 105807, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35487073

RESUMO

In response to the urgent need to encounter infection diseases, and upon increasing concerns about the devastating effects of tuberculosis (TB), the promising thiazolidin-4-one scaffold was used as a starting point to design and synthesize seventeen new compounds, relying on the pharmacophoric features of different anti-Mycobacterium tuberculosis and antibacterial active compounds. Thiazolidin-4-one was elaborated to result in bi-functioning formation, and further ring fusion into a thiazolo[3,2-a][1,3,5]triazine, which was hybridized with different heterocyclic rings and sulfonamide moieties. All the newly synthesized compounds were evaluated for their activity against drug sensitive (DS), multi-drug resistant (MDR) and extensive drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains. Additionally, their anti-bacterial activity against several bronchitis causing-bacteria (ATCC) and their antifungal activity were assessed. Several compounds showed promising results regarding all of the mentioned assays without any antifungal activities. Particularly, compound 3 showed a promising activity against the three Mtb strains (DS, MDR and XDR) with MIC of 2.49, 9.91 and 39.72 µM, respectively. Furthermore, compound 7c revealed antituberculosis activity with MIC of 2.28, 18.14 and 36.31 µM against DS, MDR and XDR strains, respectively. Both of compounds 3 and 7c surpassed azithromycin on several bronchitis causing-bacteria and showed enhanced inhibitory activity against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA), with IC50 of 3.90 and 2.47 µM, respectively. The enzymatic activity was augmented by the binding characteristics of 3 and 7c in the InhA active site. Further investigations confirmed their safety on normal cell lines, and promising predicted ADME characteristics.


Assuntos
Bronquite , Mycobacterium tuberculosis , Antifúngicos/farmacologia , Antituberculosos/química , Desenho de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Triazinas/farmacologia
7.
J Enzyme Inhib Med Chem ; 37(1): 686-700, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35139719

RESUMO

Inhibiting Cyclin-dependent kinase 2 (CDK2) has been established as a therapeutic strategy for the treatment of many cancers. Accordingly, this study aimed at developing a new set of quinazolinone-based derivatives as CDK2 inhibitors. The new compounds were evaluated for their anticancer activity against sixty tumour cell lines. Compounds 5c and 8a showed excellent growth inhibition against the melanoma cell line MDA-MB-435 with GI% of 94.53 and 94.15, respectively. Cell cycle analysis showed that compound 5c led to cell cycle cessation at S phase and G2/M phase revealing that CDK2 could be the plausible biological target. Thus, the most cytotoxic candidates 5c and 8a were evaluated in vitro for their CDK2 inhibitory activity and were able to display significant inhibitory action. The molecular docking study confirmed the obtained results. ADME study predicted that 5c had appropriate drug-likeness properties. These findings highlight a rationale for further development and optimisation of novel CDK2 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Desenvolvimento de Medicamentos , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma/metabolismo , Melanoma/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
8.
J Enzyme Inhib Med Chem ; 36(1): 384-393, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33406941

RESUMO

Joining the global fight against Tuberculosis, the world's most deadly infectious disease, herein we present the design and synthesis of novel isatin-nicotinohydrazide hybrids (5a-m and 9a-c) as promising anti-tubercular and antibacterial agents. The anti-tubercular activity of the target hybrids was evaluated against drug-susceptible M. tuberculosis strain (ATCC 27294) where hybrids 5d, 5g and 5h were found to be as potent as INH with MIC = 0.24 µg/mL, also the activity was evaluated against Isoniazid/Streptomycin resistant M. tuberculosis (ATCC 35823) where compounds 5g and 5h showed excellent activity (MIC = 3.9 µg/mL). Moreover, the target hybrids were examined against six bronchitis causing-bacteria. Most derivatives exhibited excellent antibacterial activity. K. pneumonia emerged as the most sensitive strain with MIC range: 0.49-7.81 µg/mL. Furthermore, a molecular docking study has proposed DprE1 as a probable enzymatic target for herein reported isatin-nicotinohydrazide hybrids, and explored the binding interactions within the vicinity of DprE1 active site.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Farmacorresistência Bacteriana/efeitos dos fármacos , Hidrazinas/química , Isatina/química , Mycobacterium tuberculosis/enzimologia , Oxirredutases do Álcool/química , Oxirredutases do Álcool/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Bordetella pertussis/química , Bordetella pertussis/enzimologia , Bordetella pertussis/isolamento & purificação , Bronquite/tratamento farmacológico , Bronquite/microbiologia , Desenho de Fármacos , Farmacorresistência Bacteriana/genética , Haemophilus influenzae/química , Haemophilus influenzae/enzimologia , Haemophilus influenzae/isolamento & purificação , Isoniazida/farmacologia , Klebsiella pneumoniae/química , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/isolamento & purificação , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Moraxella catarrhalis/química , Moraxella catarrhalis/enzimologia , Moraxella catarrhalis/isolamento & purificação , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/isolamento & purificação , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Streptococcus pneumoniae/química , Streptococcus pneumoniae/enzimologia , Streptococcus pneumoniae/isolamento & purificação , Estreptomicina/farmacologia , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
9.
ACS Chem Neurosci ; 14(23): 4076-4092, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-37948544

RESUMO

Epilepsy is considered one of the most common neurological disorders worldwide; it needs long-term or life-long treatment. Despite the presence of several novel antiepileptic drugs, approximately 30% patients still suffer from drug-resistant epilepsy. Subsequently, searching for new anticonvulsants with lower toxicity and better efficacy is still in paramount demand. Using target-based studies in the discovery of novel antiepileptics is uncommon owing to the insufficient information on the molecular pathway of epilepsy and complex mode of action for most of known antiepileptic drugs. In this review, we investigated the properties of anticonvulsants, types of epileptic seizures, and mechanism of action for anticonvulsants.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Humanos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Epilepsia Resistente a Medicamentos/tratamento farmacológico
10.
Eur J Med Chem ; 224: 113682, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245948

RESUMO

Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC50 = 0.140, 0.007 µm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.


Assuntos
Analgésicos/química , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Pirimidinonas/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Humanos , Masculino , Camundongos , Pirimidinonas/metabolismo , Pirimidinonas/uso terapêutico , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar
11.
Future Med Chem ; 10(1): 27-52, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29235893

RESUMO

AIM: In spite of the availability of different chemotherapies for cancer treatment, there is still a need for new candidates with higher efficacy and lower toxicity. METHODOLOGY: Aurones 7a-f, 8a-f and furoaurones 13a-f, 16a-c were synthesized. Some compounds were selected by the National Cancer Institute, USA, for cytotoxicity screening. RESULTS & DISCUSSION: The furoaurone derivative, 13a was the most active one exhibiting promising growth inhibition against leukemia, K562 and melanoma, MDA-MB-435 cells at concentration of 10 µM. It induced apoptosis in both cell lines by activation of CASP3 and inhibition of CDK2. Additionally, 13a showed good selectivity over normal kidney and liver cells. Simulation docking study was undertaken to gain insight into the possible binding mode of 13a in the CDK2 enzyme. CONCLUSION: The furoaurone 13a can be considered as a scaffold for further optimization to obtain more active hits. Graphical abstract [Formula: see text].


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA