Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 886
Filtrar
1.
Biochim Biophys Acta Gen Subj ; 1865(1): 129773, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33132199

RESUMO

BACKGROUND: Quinazolines 1 to 6, with an aromatic or aryl-vinyl substituent in position 2 are selected with the aim to compare their structures and biological activity. The selection includes a natural alkaloid, schizocommunin, and the synthetic 2-(2'-quinolyl)-3H-quinazolin-4-one, known to interact with guanine-quadruplex dependent enzymes, respectively telomerase and topoisomerase. METHODS: Breast cancer cells of the MDA cell line have been used to study the bioactivity of the tested compounds by the method of Comet Assay and FACS analyses. We model observed effects assuming stacking interactions of studied heterocycles with a naked skeleton of G-quadruplex, consisting of guanine quartet layers and potassium ions. Interaction energies are computed using a dispersion corrected density functional theory method, and an electron-correlated molecular orbital theory method. RESULTS: Selected compounds do not remarkably delay nor change the dynamics of cellular progression through the cell cycle phases, while changing significantly cell morphology. Our computational models quantify structural effects on heterocyclic G4-complex stabilization energies, which directly correlate with observed biological activity. CONCLUSION: Our computational model of G-quadruplexes is an acceptable tool for the study of interaction energies of G-quadruplexes and heterocyclic ligands, predicting, and allowing design of novel structures. GENERAL SIGNIFICANCE: Genotoxicity of quinazolin-4-one analogues on human breast cancer cells is not related to molecular metabolism but rather to their interference with G-quadruplex regulatory mechanisms. Computed stabilization energies of heterocyclic ligand complexes of G-quadruplexes might be useful in the prediction of novel telomerase / helicase, topoisomerase and NA polymerase dependent drugs.


Assuntos
Quadruplex G/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Humanos , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Quinazolinonas/química , Quinazolinonas/farmacologia , Telômero/química
2.
Front Immunol ; 11: 2094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973818

RESUMO

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1ß, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.


Assuntos
Betacoronavirus , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Butirofenonas/farmacologia , Butirofenonas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Infecções por Coronavirus/virologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Pandemias , Peptidil Dipeptidase A/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pneumonia Viral/virologia , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
3.
BMC Neurol ; 20(1): 353, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32962663

RESUMO

BACKGROUND: Dynamic-related protein 1 (Drp1) is a key protein involved in the regulation of mitochondrial fission, and it could affect the dynamic balance of mitochondria and appears to be protective against neuronal injury in epileptic seizures. Equilibrative nucleoside transporter 1 (ENT1) is expressed and functional in the mitochondrial membrane that equilibrates adenosine concentration across membranes. Whether Drp1 participates in the pathogenesis of epileptic seizures via regulating function of ENT1 remains unclear. METHODS: In the present study, we used pilocarpine to induce status epilepticus (SE) in rats, and we used mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor to Drp1, to suppress mitochondrial fission in pilocarpine-induced SE model. Mdivi-1administered by intraperitoneal injection before SE induction, and the latency to firstepileptic seizure and the number of epileptic seizures was thereafter observed. The distribution of Drp1 was detected by immunofluorescence, and the expression patterns of Drp1 and ENT1 were detected by Western blot. Furthermore, the mitochondrial ultrastructure of neurons in the hippocampal CA1 region was observed by transmission electron microscopy. RESULTS: We found that Drp1 was expressed mainly in neurons and Drp1 expression was significantly upregulated in the hippocampal and temporal neocortex tissues at 6 h and 24 h after induction of SE. Mitochondrial fission inhibitor 1 attenuated epileptic seizures after induction of SE, reduced mitochondrial damage and ENT1 expression. CONCLUSIONS: These data indicate that Drp1 is upregulated in hippocampus and temporal neocortex after pilocarpine-induced SE and the inhibition of Drp1 may lead to potential therapeutic target for SE by regulating ENT1 after pilocarpine-induced SE.


Assuntos
Dinaminas/antagonistas & inibidores , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Quinazolinonas/farmacologia , Estado Epiléptico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/metabolismo
4.
Cardiovasc Ther ; 2020: 9397109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821285

RESUMO

Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Quinazolinonas/farmacologia , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Proteína C-Reativa/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Endotoxemia/genética , Endotoxemia/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas , Componente Amiloide P Sérico/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismo
5.
J Med Chem ; 63(17): 9838-9855, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32809827

RESUMO

Redox modulators have been developed as an attractive approach to treat cancer. Herein, we report the synthesis, identification, and biological evaluation of a quinazolinedione reactive oxygen species (ROS) inducer, QD394, with significant cytotoxicity in pancreatic cancer cells. QD394 shows a transcriptomic profile remarkably similar to napabucasin, a cancer stemness inhibitor. Both small molecules inhibit STAT3 phosphorylation, increase cellular ROS, and decrease the GSH/GSSG ratio. Moreover, QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1, two proteins involved in mitochondrial RNA catabolic processes and both negatively correlated with the overall survival of pancreatic cancer patients. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Ferro/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Quinazolinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Naftoquinonas/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/toxicidade
6.
J Med Chem ; 63(17): 9752-9772, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32697083

RESUMO

DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.


Assuntos
Dano ao DNA , Desenho de Fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , RecQ Helicases/antagonistas & inibidores , Telômero/genética , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Sinergismo Farmacológico , Células HCT116 , Humanos , Modelos Moleculares , Conformação Proteica , Quinazolinonas/química , RecQ Helicases/química , Relação Estrutura-Atividade
7.
An Acad Bras Cienc ; 92(2): e20180168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520214

RESUMO

Meta-analysis is a probabilistic technique that combines results from several studies that approach the same topic and produce a result that sums up the whole. In the agricultural field, it is used to make empirical estimates of efficiency for the development of productivity and economic research on agriculture. Meta-analysis can be applied through software such as R, which is executed through commands, and produces results without providing user interactivity, nor does it reproduce a friendly and easy-to-understand interface. This paper presents the creation of a computer system, the WMA, which aims to simplify the execution of meta-analysis, providing a graphical interface and improves the display of the results through an interactive visualization using the Hierarchical Information Visualization Technique Bifocal Tree. For validation, the meta-analysis was applied in the agricultural area in a case study that grouped studies that used the fungicide fluquinconazole to combat the soybean rust disease, the results obtained through the application of the meta-analysis were analyzed using the WMA proposed tool.


Assuntos
Phakopsora pachyrhizi/efeitos dos fármacos , Quinazolinonas/farmacologia , Software , Triazóis/farmacologia , Reprodutibilidade dos Testes
8.
Parasitol Res ; 119(7): 2327-2335, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32476058

RESUMO

Acanthamoeba castellanii is a free-living amoeba which can cause a blinding keratitis and fatal granulomatous amoebic encephalitis. The treatment of Acanthamoeba infections is challenging due to formation of cyst. Quinazolinones are medicinally important scaffold against parasitic diseases. A library of nineteen new 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives was synthesized to evaluate their antiamoebic activity against Acanthamoeba castellanii. One-pot synthesis of 3-aryl-6,7-dimethoxyquinazolin-4(3H)-ones (1-19) was achieved by reaction of 2-amino-4,5-dimethoxybenzoic acid, trimethoxymethane, and different substituted anilines. These compounds were purified and characterized by standard chromatographic and spectroscopic techniques. Antiacanthamoebic activity of these compounds was determined by amoebicidal, encystation, excystation and host cell cytopathogenicity in vitro assays at concentrations of 50 and 100 µg/mL. The IC50 was found to be between 100 and 50 µg/mL for all the compounds except compound 5 which did not exhibit amoebicidal effects at these concentrations. Furthermore, lactate dehydrogenase assay was also performed to evaluate the in vitro cytotoxicity of these compounds against human keratinocyte (HaCaT) cells. The results revealed that eighteen out of nineteen derivatives of quinazolinones significantly decreased the viability of A. castellanii. Furthermore, eighteen out of nineteen tested compounds inhibited the encystation and excystation, as well as significantly reduced the A. castellanii-mediated cytopathogenicity against human cells. Interestingly, while tested against human normal cell line HaCaT keratinocytes, all compounds did not exhibit any overt cytotoxicity. Furthermore, a detailed structure-activity relationship is also studied to optimize the most potent hit from these synthetic compounds. This report presents several potential lead compounds belonging to 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives for drug discovery against infections caused by Acanthamoeba castellanii.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/química , Amebicidas/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Acanthamoeba castellanii/crescimento & desenvolvimento , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Amebicidas/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Encistamento de Parasitas/efeitos dos fármacos , Quinazolinonas/síntese química , Relação Estrutura-Atividade
9.
Int J Nanomedicine ; 15: 3161-3180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440116

RESUMO

Aim: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. Materials and Methods: Novel quinazolinone-benzenesulfonamide derivatives 5-18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase. Results: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 µg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. Conclusion: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.


Assuntos
Antibacterianos/farmacologia , Quinazolinonas/farmacologia , Sulfonamidas/farmacologia , Tioacetamida/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Cobre/farmacologia , DNA Girase/metabolismo , Raios gama , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Quinazolinonas/síntese química , Quinazolinonas/química , Sulfonamidas/síntese química , Sulfonamidas/química , Tioacetamida/síntese química , Tioacetamida/química , Inibidores da Topoisomerase II/farmacologia
10.
Eur J Med Chem ; 200: 112318, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470709

RESUMO

A series of octahydroquinazoline-5-ones (OHQs 1-50) were designed and synthesized via an improved five-component reaction (5CR). Their bioactivities against dengue virus (DENV) were evaluated by determining lacate dehydrogenase (LDH) in the BHK-21 cells infected with DENV-2. Primary structure-activity relationship showed that six of OHQs with suitable substituents displayed good activities with EC50 = 1.31-1.85 µM. The primary bioactivity mechanism was investigated using the most potent OHQ 23. Experimental results indicate that 23 could efficiently reverse the DENV-2-induced cytopathic effect and suppress the expression of viral structure E protein, but showed no interaction with the MTase and RdRp domain of NS5, a protein plays an important role in viral genome transcription and viral protein translation. The efficient synthetic method, novel structures as DENV inhibitors and good activities are expected to be developed potential DENV inhibitors.


Assuntos
Vírus da Dengue/efeitos dos fármacos , Quinazolinonas/farmacologia , Linhagem Celular , Dengue/tratamento farmacológico , Humanos , Lactato Desidrogenases/análise , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/efeitos dos fármacos , Proteínas Estruturais Virais/antagonistas & inibidores , Replicação Viral
11.
Eur J Med Chem ; 197: 112333, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32361176

RESUMO

In order to discover new antioxidants, fifteen novel quinazolinone derivatives bearing benzenesulfonamide moiety with variable heterocyclic tail, were synthesized and their structures were established on the basis of spectral data. All the synthesized compounds were screened for their antioxidant potential using DPPH assay in comparison to ascorbic acid. The N-(pyrazin-2-yl)-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide 16 was the most active scaffold in this series with greater scavenging activity than that of ascorbic acid. In vivo acute toxicity study of compound 16 indicates its relative safety with a median lethal dose of 200 mg/kg. The possible antioxidant and hepatoprotective activities of compound 16 were evaluated in irradiated mice. Compound 16 caused mitigation of gamma radiation-induced oxidative stress verified by the decline in MDA, ROS and NF-κB levels. Moreover, SOD and PON1 activities, as well as Zn2+ levels, were improved in liver tissues. Furthermore, molecular docking of compound 16 inside the active site of SOD and PON1 demonstrated the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings support that compound 16 may represent a structural lead for developing new antioxidants and hepatoprotective agents.


Assuntos
Depuradores de Radicais Livres/farmacologia , Fígado/efeitos dos fármacos , Quinazolinonas/farmacologia , Protetores contra Radiação/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Arildialquilfosfatase/química , Arildialquilfosfatase/metabolismo , Domínio Catalítico , Depuradores de Radicais Livres/síntese química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Subunidade p50 de NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Quinazolinonas/síntese química , Protetores contra Radiação/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo
12.
J Med Chem ; 63(10): 5287-5296, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343145

RESUMO

We report herein the syntheses of 79 derivatives of the 4(3H)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant Staphylococcus aureus (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound 73 ((E)-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound 73 to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the ß-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Antibacterianos/uso terapêutico , Feminino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana/métodos , Neutropenia/tratamento farmacológico , Neutropenia/microbiologia , Quinazolinonas/uso terapêutico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Relação Estrutura-Atividade
13.
Proc Natl Acad Sci U S A ; 117(16): 8900-8911, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32253314

RESUMO

Signaling pathways that sense amino acid abundance are integral to tissue homeostasis and cellular defense. Our laboratory has previously shown that halofuginone (HF) inhibits the prolyl-tRNA synthetase catalytic activity of glutamyl-prolyl-tRNA synthetase (EPRS), thereby activating the amino acid response (AAR). We now show that HF treatment selectively inhibits inflammatory responses in diverse cell types and that these therapeutic benefits occur in cells that lack GCN2, the signature effector of the AAR. Depletion of arginine, histidine, or lysine from cultured fibroblast-like synoviocytes recapitulates key aspects of HF treatment, without utilizing GCN2 or mammalian target of rapamycin complex 1 pathway signaling. Like HF, the threonyl-tRNA synthetase inhibitor borrelidin suppresses the induction of tissue remodeling and inflammatory mediators in cytokine-stimulated fibroblast-like synoviocytes without GCN2, but both aminoacyl-tRNA synthetase (aaRS) inhibitors are sensitive to the removal of GCN1. GCN1, an upstream component of the AAR pathway, binds to ribosomes and is required for GCN2 activation. These observations indicate that aaRS inhibitors, like HF, can modulate inflammatory response without the AAR/GCN2 signaling cassette, and that GCN1 has a role that is distinct from its activation of GCN2. We propose that GCN1 participates in a previously unrecognized amino acid sensor pathway that branches from the canonical AAR.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Aminoácidos/metabolismo , Aminoacil-tRNA Sintetases/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/cirurgia , Linhagem Celular , Fibroblastos , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Pulmão/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Piperidinas/uso terapêutico , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinonas/uso terapêutico , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA-Seq , Transdução de Sinais/imunologia , Membrana Sinovial/citologia , Membrana Sinovial/patologia , Sinoviócitos , Transativadores/genética , Transativadores/metabolismo
14.
J Agric Food Chem ; 68(19): 5302-5308, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32298097

RESUMO

A series of novel quinazolinone sulfide derivatives containing a dithioacetal moiety were designed and synthesized using Tomato chlorosis virus coat protein (ToCVCP) as a potential drug target, and the inhibitory effect of ToCV was systematically evaluated in vitro and in vivo. The experimental results showed that most of the compounds presented a strong affinity. Notably, the binding abilities of compounds D8 and D16 to ToCVCP both reached a micromolar level, which were 0.19 and 0.83 µM, respectively. The relative expression level of ToCVCP gene was detected using real-time quantitative polymerase chain reaction in Nicotiana benthamiana. Compounds D8 and D16 significantly reduced the relative expression level of ToCVCP gene by 93.34 and 83.47%, respectively, which were better than those of conventional antiviral agents. This study lays a good foundation for the structural design and modification of quinazolinone sulfide derivatives as anti-ToCV drugs.


Assuntos
Antivirais/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Crinivirus/efeitos dos fármacos , Quinazolinonas/farmacologia , Sulfetos/farmacologia , Antivirais/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Crinivirus/genética , Crinivirus/metabolismo , Doenças das Plantas/virologia , Quinazolinonas/química , Sulfetos/química , Tabaco/virologia
15.
J Agric Food Chem ; 68(20): 5539-5544, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32323987

RESUMO

Tomato chlorosis virus (ToCV) has caused great harm to the production of tomato worldwide. To develop efficient anti-ToCV agents, some novel 4(3H)-quinazolinone derivatives containing dithioacetal were designed and synthesized, and their anti-ToCV activities were evaluated by microscale thermophoresis (MST) using ToCV coat protein (ToCV-CP) as a new target. The results showed that some compounds had a strong binding capacity to ToCV-CP. In particular, compounds C5 and C22 have an excellent binding capacity to ToCV-CP, with binding constant values of 0.24 and 0.25 µM, respectively. Additionally, reduced ToCV-CP gene expression levels of 81.05 and 87.59% could be achieved when tomato was treated with compounds C5 and C22, respectively, which were obviously higher than the levels after ningnanmycin (NNM) treatment (43.88%) and lead compound Xiangcaoliusuobingmi (XCLSBM) treatment (63.56%). Therefore, this work indicates that 4(3H)-quinazolinone derivatives containing dithioacetal moiety can be used as novel anti-ToCV agents.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Crinivirus/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Antivirais/química , Crinivirus/genética , Crinivirus/fisiologia , Desenho de Fármacos , Lycopersicon esculentum/virologia , Estrutura Molecular , Doenças das Plantas/virologia , Relação Estrutura-Atividade
16.
J Enzyme Inhib Med Chem ; 35(1): 733-743, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32189526

RESUMO

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2-20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (KIs; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12-17, and 19-20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27-195 and 3.2-19, respectively, while compounds 12, 14-17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48-158 and 5.4-31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.HighlightsQuinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised.The new molecules potently inhibited the hCA isoforms I, II, IV, and IX.Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 12-17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 12, 14-17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12-17, and 19-20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14-17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Quinazolinonas/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/química , Relação Estrutura-Atividade , Sulfonamidas/química
17.
Br J Cancer ; 122(9): 1288-1297, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32147668

RESUMO

BACKGROUND: Previous studies suggested that mdivi-1 (mitochondrial division inhibitor), a putative inhibitor of dynamin-related protein (DRP1), decreased cancer cell proliferation through inducing mitochondrial fusion and altering oxygen consumption. However, the metabolic reprogramming underlying the DRP1 inhibition is still unclear in cancer cells. METHODS: To better understand the metabolic effect of DRP1 inhibition, [U-13C]glucose isotope tracing was employed to assess mdivi-1 effects in several cancer cell lines, DRP1-WT (wild-type) and DRP1-KO (knockout) H460 lung cancer cells and mouse embryonic fibroblasts (MEFs). RESULTS: Mitochondrial staining confirmed that mdivi-1 treatment and DRP1 deficiency induced mitochondrial fusion. Surprisingly, metabolic isotope tracing found that mdivi-1 decreased mitochondrial oxidative metabolism in the lung cancer cell lines H460, A549 and the colon cancer cell line HCT116. [U-13C]glucose tracing studies also showed that the TCA cycle intermediates had significantly lower enrichment in mdivi-1-treated cells. In comparison, DRP1-WT and DRP1-KO H460 cells had similar oxidative metabolism, which was decreased by mdivi-1 treatment. Furthermore, mdivi-1-mediated effects on oxidative metabolism were independent of mitochondrial fusion. CONCLUSIONS: Our data suggest that, in cancer cells, mdivi-1, a putative inhibitor of DRP1, decreases oxidative metabolism to impair cell proliferation.


Assuntos
Dinaminas/genética , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quinazolinonas/farmacologia , Células A549 , Animais , Isótopos de Carbono/química , Isótopos de Carbono/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Dinaminas/antagonistas & inibidores , Técnicas de Inativação de Genes , Glucose/química , Glucose/farmacologia , Células HCT116 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos
18.
J Med Chem ; 63(8): 4256-4292, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32212730

RESUMO

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.


Assuntos
Desenho de Fármacos , Inibidores de Histona Desacetilases/síntese química , Ácidos Hidroxâmicos/síntese química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Quinazolinonas/síntese química , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Células HEK293 , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Estrutura Terciária de Proteína , Quinazolinonas/farmacologia , Ratos
19.
Oncol Rep ; 43(3): 1010-1018, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020220

RESUMO

The efficacy of chemotherapy for hepatocellular carcinoma (HCC) remains unsatisfactory, primarily due to inherent self­defense mechanisms (e.g., mitophagy and autophagy). In the present study, we aimed to explore the pro­apoptotic effects of targeting mitophagy to potentiate the efficacy of chemotherapy for HCC. HCC cells were subjected to cisplatin, after which cisplatin­induced mitophagy was quantified by immunofluorescence. Mdivi­1, a specific dynamin­related protein 1 (DRP1) inhibitor, was used to study the role of DRP1 in cisplatin­induced HCC mitophagy. The synergistic effect of cisplatin and the DRP1 inhibitor on HCC was assessed in vitro and in vivo. Accordingly, cisplatin induced mitophagy in surviving HCC cells by activating DRP1. The DRP1 inhibitor (Mdivi­1) increased the apoptosis of cisplatin­treated HCC cells by targeting mitophagy. Mechanistically, Mdivi­1 upregulated Bax and downregulated Bcl­xL, leading to an increase in mitochondrial membrane permeability and subsequent release of cytochrome c from mitochondria into the cytosol, thereby aggravating cisplatin­induced apoptosis in HCC cells. Moreover, Mdivi­1 acted synergistically with cisplatin to suppress HCC xenograft growth in vivo. Our results indicate that targeting cisplatin­mediated mitophagy increases HCC apoptosis via DRP1 inhibition, providing preclinical proof of concept for combination therapy targeting mitophagy to potentiate the efficacy of chemotherapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/farmacologia , Dinaminas/genética , Neoplasias Hepáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dinaminas/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Quinazolinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Toxicology ; 433-434: 152394, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32027962

RESUMO

Nongenotoxic chemicals can produce liver tumours in rats and mice by a mitogenic mode of action involving activation of the constitutive androstane receptor (CAR). The aim of this study was to evaluate the usefulness of cultured hepatocytes from normal (wild type; WT) and CAR knockout (KO) rats to screen compounds as potential activators of rat CAR and to validate this test system. Cultured hepatocytes from male Sprague-Dawley WT and CAR KO rats were treated with either 100 and 1000 µM sodium phenobarbital (NaPB), 3-100 µM fluquinconazole (FQZ), or 3-300 µM 3-(difluoromethyl)-1-methyl-N-(3´,4´,6-trifluoro[1,1´-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (TI1) for 96 h. Induction of cytochrome P450 (CYP) enzymes was monitored by measurement of 7-pentoxyresorufin O-depentylase (PROD), 7-benzyloxyresorufin O-debenzylase (BROD) and 7-benzyloxyquinoline O-debenzylase (BQ) activities. Hepatocytes undergoing replicative DNA synthesis (RDS) were labelled by adding 10 µM 5-bromo-2´-deoxyuridine to the culture medium for determination of the hepatocyte labelling index. The treatment of WT, but not of CAR KO, rat hepatocytes with NaPB, FQZ and TI1 increased hepatocyte RDS and induced CYP2B-dependent PROD activity. In contrast, all three compounds increased CYP2B/3A-dependent BROD and CYP3A-dependent BQ activities in both WT and CAR KO rat hepatocytes. Hepatocyte RDS was increased in both WT and CAR KO rat hepatocytes by treatment with 25 ng/ml epidermal growth factor as a positive control. Overall, these results demonstrate that the effects of three CAR activators on RDS and CYP2B enzyme induction are abolished in cultured CAR KO rat hepatocytes. As demonstrated by this validation study, the CAR KO hepatocyte model is a useful in vitro mechanistic tool for the rapid screening of chemicals as potential activators of rat CAR.


Assuntos
Hepatócitos/efeitos dos fármacos , Fenobarbital/farmacologia , Quinazolinonas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Triazóis/farmacologia , Animais , Indutores das Enzimas do Citocromo P-450/administração & dosagem , Indutores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , DNA/metabolismo , Relação Dose-Resposta a Droga , Técnicas de Inativação de Genes , Masculino , Camundongos Knockout , Fenobarbital/administração & dosagem , Quinazolinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Triazóis/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA