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1.
Eur J Med Chem ; 181: 111583, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400710

RESUMO

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Desenho de Drogas , Feminino , Humanos , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Inibidores da Topoisomerase I/química , Moduladores de Tubulina/química
2.
Eur J Med Chem ; 182: 111575, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415900

RESUMO

We report one-pot synthesis of a series of new 3-aryl-8-methylquinazolin-4(3H)-ones (QNZ) and their antimicrobial activity against Acanthamoeba castellanii belonging to T4 genotype. A library of fifteen synthetic derivatives of QNZs was synthesized, and their structural elucidation was performed by using nuclear magnetic resonance (NMR) spectroscopy and electron impact mass spectrometry (EI-MS). Elemental analyses and high-resolution mass spectrometry data of all derivatives were found to be in agreeable range. Amoebicidal assays performed at concentrations ranging from 50 to 100 µg/mL revealed that all derivatives of QNZ significantly decreased the viability of A. castellanii and QNZ 2, 5, 8, and 13 were found to have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 and 15 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, several QNZs inhibited the encystation and excystationas as well as abolished A. castellanii-mediated host cells cytopathogenicity in human cells. Whereas, these QNZs showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii. A brief structure-activity relationship is also developed to optimize the hit of most potent compounds from the library. To the best of our knowledge, it is first of its kind medicinal chemistry approach on a single class of compounds i.e., quinazolinone against keratitis and brain infection causing free-living amoeba, A. castellanii.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Quinazolinonas/farmacologia , Amebicidas/síntese química , Amebicidas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
3.
Biophys Chem ; 253: 106220, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302375

RESUMO

Stabilization of G-quadruplex structures in the c-KIT promoter with the aid of ligands has become an area of great interest in potential cancer therapeutics. Understanding the binding process between ligands and G-quadruplex is essential for a discovery of selective ligands with high binding affinity to G-quadruplex. In the present work, binding mechanisms of 4-quinazolinones to c-KIT G-quadruplex were investigated theoretically by means of molecular dynamics (MD) simulations. To explore the binding affinity of ligands, binding free energy calculations were performed using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. We demonstrate that the key interactions in G-quadruplex-ligand complexes are π-π stacking and hydrogen bond interactions. However, neither of these two interactions alone determines the stability of the G-quadruplex-ligand complexes; rather, it is the result of an intricate interplay between the two. To further examine the nature of the binding, a free energy decomposition analysis at residue level was carried out. The results clearly demonstrate the crucial roles of two hot spot residues (DG4 and DG8) for the binding of ligands to c-KIT G-quadruplex, and highlight the importance of the planar aromatic moiety of ligands in G-quadruplex stabilization via π-π stacking interactions. Our study can assist in the design of new derivatives of 4-quinazolinone with high binding affinity for c-KIT G-quadruplex.


Assuntos
Proteínas Proto-Oncogênicas c-kit/química , Quinazolinonas/química , Termodinâmica , Sítios de Ligação , Quadruplex G , Ligações de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular
4.
Eur J Med Chem ; 175: 287-308, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096152

RESUMO

Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 µg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 µg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4'c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ∼2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 µg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 µg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Animais , Antibacterianos/química , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Quinazolinonas/química , Relação Estrutura-Atividade , Células Vero
5.
Artigo em Inglês | MEDLINE | ID: mdl-31082683

RESUMO

Thiazolidinediones and quinazolin-4-ones compounds, previously known for their activity against Type 2 diabetes and antifungal activity respectively, are currently being investigated for their anti-cancer activity. The determination of pharmacokinetic parameters for these two classes of compounds using a simultaneous chromatographic method with a low detection limit is a challenge. In this study, a highly sensitive and simultaneous LC-MS/MS-based bioanalytical method was developed and validated in rat plasma for the estimation of four novel anti-cancer compounds, BIT-15-67 and BNT-11, belonging to the Thiazolidinedione class, and BNUA-108 and BNUA-48, from the quinazolin-4-one class. The analytes were extracted from plasma samples by protein precipitation and separated on a short reverse phase Hypersil Phenyl BDS, 50 × 4.6 mm, 2.4 µm column at a column oven temperature of 40 °C. An isocratic mobile phase, a 20:80 (v/v) mixture of 5 mM ammonium acetate solution and acetonitrile containing 0.1% formic acid, was used for the elution at a flow rate of 0.4 mL/min. The analytes and internal standard, sulfaphenazole, were quantified in the multiple reaction monitoring mode using positive electrospray ionization with specific pair of mass by charge ratio. All standard validation parameters were assessed as per current bioanalytical method validation guidelines in rat plasma. The area response for the four analytes was found to be linear over the concentration range of 1.00 to 1000 ng/mL in rat plasma. The signal to noise at LLOQ of 1 ng/mL was adequate for application to different pre-clinical studies. The intra- and inter-day precision were <11% and accuracy deviated -1.8 to 9.60% from the nominal. The mean recovery was high (about 90%) and consistent for all the analytes over the linear dynamic range of the method. This simple, robust and validated method can be employed to determine the rat plasma concentrations of the four selected anticancer compounds in preclinical studies such as the pharmacodynamic and the pharmacokinetic studies including tissue distribution and excretion, and the toxicokinetic studies. In this study, pharmacokinetic parameters were determined using this method for all the four compounds individually following intravenous administration in rats.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Quinazolinonas/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/sangue , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
6.
Eur J Med Chem ; 176: 41-49, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091479

RESUMO

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC50 values of 1.54 µM and 0.71 µM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC50 values of 1.90 and 0.84 µM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinazolinonas/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação , Replicação do DNA/efeitos dos fármacos , Células Hep G2 , Antígenos do Núcleo do Vírus da Hepatite B/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade
7.
J Enzyme Inhib Med Chem ; 34(1): 1030-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074303

RESUMO

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
8.
Carbohydr Res ; 478: 10-17, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039450

RESUMO

A series of novel tricyclic quinazolinone-iminosugars 1 (a-c) were synthesized from the benzyl protected sugars through three steps. Firstly, the benzyl protected sugar (aldehyde) 5 reacted with o-aminobenzamide by the iodine-induced oxidative condensation to afford the corresponding aldo-quizanolinone 6. Secondly, through the intramolecular cyclization of the unprotected OH and the amide NH in 6, the tricyclic compounds 7 and 8 were constructed by the key Mitsunobu reaction. Finally, removal of the benzyl group gave the target tricyclic quinazolinone-iminosugars 1. The protocol was effective for the preparation of the tricyclic iminosugars in satisfactory yield. Interestingly, an unusual C-2 epimerization was observed with d-mannose and d-ribose compounds under the conditions of the Mitsunobu reaction that generated the products having the trans configuration at the C-2 and C-3 positions. Unfortunately, such tricyclic quinazolinone-iminosugars showed no inhibitory effects on the tested five glycosidases.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/farmacologia , Quinazolinonas/farmacologia , Aspergillus niger/enzimologia , Canavalia/enzimologia , Configuração de Carboidratos , Café/enzimologia , Ciclização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Glicosídeo Hidrolases/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/química , Prunus dulcis/enzimologia , Quinazolinonas/síntese química , Quinazolinonas/química
9.
Org Lett ; 21(8): 2855-2858, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30933523

RESUMO

Furylimines of aromatic o-nitro aldehydes undergo a photoinduced cascade transformation offering rapid atom- and step-economical access to complex polyheterocyclic scaffolds possessing a privileged pyrroloquinazolinone core.


Assuntos
Alcaloides/química , Pirróis/química , Quinazolinonas/química , Aldeídos/química , Catálise , Ciclização , Iminas/química , Oxirredução , Processos Fotoquímicos , Polímeros/química , Estereoisomerismo
10.
Eur J Med Chem ; 172: 26-35, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30939351

RESUMO

Nowadays, due to spreading antibiotic resistance among clinically relevant pathogens, the requirement of novel therapeutic approaches is felt more than ever. One of the alternative strategies is anti-virulence therapy without affecting bacterial growth or viability. In Pseudomonas aeruginosa, an opportunistic human pathogen that exhibits intrinsic multi-drug resistance, both virulence factors' production and biofilm formation depends on its quorum sensing (QS) network. Therefore, targeting the key proteins involved in QS system is an attractive method to overcome P. aeruginosa pathogenicity and resistance. The transcriptional regulator PqsR, also called MvfR, is one of these major proteins which employs 3,4-dihydroxy-2-heptylquinoline (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signaling molecules. Reviewing the advances in development of small molecules inhibit this protein, assist to open a new window to smart molecule design that may revolutionize treatment of P. aeruginosa infections.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , Quinazolinonas/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinolonas/síntese química , Quinolonas/química , Percepção de Quorum/efeitos dos fármacos , Transativadores
11.
Eur J Med Chem ; 173: 185-202, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31003060

RESUMO

A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Quinazolinonas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , 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 , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinonas/química , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
12.
J Enzyme Inhib Med Chem ; 34(1): 808-817, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30879350

RESUMO

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.


Assuntos
Cumarínicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-Atividade
13.
J Enzyme Inhib Med Chem ; 34(1): 672-683, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30821525

RESUMO

Some new 3H-quinazolin-4-one derivatives were synthesised and screened for anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities. Compound 15d was more potent in reducing the cell viabilities of HT-29 and SW620 cells lines to 38%, 36.7%, compared to 5-FU which demonstrated cell viabilities of 65.9 and 42.7% respectively. The IC50 values of 15d were ∼20 µg/ml. Assessment of apoptotic activity revealed that 15d decreased the cell viability by down regulating Bcl2 and BclxL. Moreover, compounds, 8j, 8d/15a/15e, 5b, and 8f displayed lowered IC50 values than oleanolic acid against proinflammatory isoforms of hGV, hG-X, NmPLA2, and AmPLA2. In addition, 8d, 8h, 8j, 15a, 15b, 15e, and 15f showed better anti-α-amylase than quercetin, whereas 8g, 8h, and 8i showed higher anti-α-glucosidase activity than allopurinol. Thus, these compounds can be considered as potential antidiabetic agents. Finally, none of the compounds showed higher antiproteases or xanthine oxidase activities than the used reference drugs.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Peptídeo Hidrolases/metabolismo , Fosfolipases/antagonistas & inibidores , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HT29 , Humanos , Síndrome Metabólica/metabolismo , Estrutura Molecular , Fosfolipases/metabolismo , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Eur J Med Chem ; 170: 157-172, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884322

RESUMO

Emergence of drug resistance has created unmet medical need for the development of new classes of antibiotics. Discovery of new antibacterial agents with new mode of action remains a high priority universally. 4(3H)-quinazolinone, a fused nitrogen heterocyclic compound has emerged as a biologically privileged structure, possessing a wide range of biological properties viz. anticancer, antibacterial, antitubercular, antifungal, anti-HIV, anticonvulsant, anti-inflammatory and analgesic activities. Promising antibacterial properties of quinazolinones have enthused the medicinal chemists to explore and develop this fused heterocyclic system for new antibacterial agents. Utilization of quinazolinone core for the design and synthesis of new antibacterial agents has recently gained momentum. This review aims to provide an overview of the structures and antibacterial activity of various 4(3H)-quinazolinone derivatives covering various aspects of in vitro and in vivo pharmacological activities and structure activity relationships (SARs).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Antibacterianos/uso terapêutico , Descoberta de Drogas/métodos , Humanos , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade
15.
Biomed Chromatogr ; 33(5): e4511, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30773664

RESUMO

The purpose of this study was to develop and validate an LC-MS/MS method for simultaneous determination of idelalisib and GS-563117 in dog plasma. The analytes were extracted using ethyl acetate and then separated on a Waters Acquity UPLC BEH C18 column (50 × 2.1 mm, i. d., 1.7 µm) using 0.1% formic acid in water and acetonitrile as mobile phase at a flow rate of 0.3 mL/min in gradient elution mode. The analytes were quantified using selected reaction monitoring with precursor-to-product transitions at m/z 416.2 → 176.1, m/z 432.2 → 192.1 and m/z 421.2 → 176.1 for idelalisib, GS-563117 and [2 H5 ]-idelalisib (internal standard). The assay showed good linearity (r > 0.9992) over the tested concentration range of 0.1-600 ng/mL for idelalisib and 0.1-300 ng/mL for GS-563117. The intra- and inter-day RSD values for idelalisib and GS-563117 were <8.84 and 12.41%, respectively. The intra- and inter-day RE values were within the range of -7.21-8.52%, and -6.44-14.23%, respectively. The extraction recovery was found to be >84.59% and no matrix effects were observed. The validated LC-MS/MS method has been successfully applied for the simultaneous determination of idelalisib and GS-563117 in a pharmacokinetic study in dogs. Our results suggested that idelalisib was rapidly metabolized into its metabolite GS-563117 in dog and the in vivo exposure of GS-563117 was 17.59% of that of idelalisib.


Assuntos
Cromatografia Líquida/métodos , Purinas/sangue , Purinas/metabolismo , Quinazolinonas/sangue , Quinazolinonas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Purinas/química , Purinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Reprodutibilidade dos Testes
16.
Eur J Pharm Sci ; 131: 177-194, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776468

RESUMO

Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in 'suspension' for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3-1.7 µM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays' potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.


Assuntos
Citocromo P-450 CYP1A1 , Citocromo P-450 CYP1B1 , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Quinazolinonas , Antineoplásicos/farmacologia , Benzo(a)pireno/toxicidade , Bioensaio , Linhagem Celular , Cisplatino/farmacologia , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/química , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/antagonistas & inibidores , Citocromo P-450 CYP1B1/química , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Quinazolinonas/química , Quinazolinonas/farmacologia
17.
J Ind Microbiol Biotechnol ; 46(3-4): 483-492, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30729343

RESUMO

Actinobacteria are a major source of novel bioactive natural products. A challenge in the screening of these microorganisms lies in finding the favorable growth conditions for secondary metabolite production and dereplication of known molecules. Here, we report that Streptomyces sp. MBT27 produces 4-quinazolinone alkaloids in response to elevated levels of glycerol, whereby quinazolinones A (1) and B (2) form a new sub-class of this interesting family of natural products. Global Natural Product Social molecular networking (GNPS) resulted in a quinazolinone-related network that included anthranilic acid (3), anthranilamide (4), 4(3H)-quinazolinone (5), and 2,2-dimethyl-1,2-dihydroquinazolin-4(3H)-one (6). Actinomycins D (7) and X2 (8) were also identified in the extracts of Streptomyces sp. MBT27. The induction of quinazolinone production by glycerol combined with biosynthetic insights provide evidence that glycerol is integrated into the chemical scaffold. The unprecedented 1,4-dioxepane ring, that is spiro-fused into the quinazolinone backbone, is most likely formed by intermolecular etherification of two units of glycerol. Our work underlines the importance of varying the growth conditions for the discovery of novel natural products and for understanding their biosynthesis.


Assuntos
Descoberta de Drogas , Quinazolinonas/química , Streptomyces/química , Produtos Biológicos/química , Fermentação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , ortoaminobenzoatos/química
18.
Org Biomol Chem ; 17(12): 3118-3128, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30730519

RESUMO

An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low yielding by previous methods. This synthetic approach, exemplified with 24 amidines and requiring only a single purification, highlights a multicomponent Ugi-Mumm rearrangement to afford highly diversified quinazolinones which undergo regiospecific rearrangement to afford new amidines. The method extensively broadens the structural scope of this new class of trisubstituted amidines and demonstrates the tolerance of regional C3 amidine steric bulk, visualized with X-ray crystallographic analysis.


Assuntos
Amidinas/síntese química , Quinazolinonas/química , Amidinas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
19.
Eur J Med Chem ; 165: 115-132, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665142

RESUMO

Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 µM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 µM and >50 µM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 µM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.


Assuntos
Antineoplásicos/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinazolinonas/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Polimerização/efeitos dos fármacos , Quinazolinonas/química , Bibliotecas de Moléculas Pequenas , Tubulina (Proteína)/metabolismo
20.
Chem Biodivers ; 16(4): e1800502, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30653817

RESUMO

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10-0.16 µm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29-3.67 µm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21-0.38 µm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Quinazolinonas/farmacologia , 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 , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
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