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1.
Arch Virol ; 165(3): 683-690, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32002668

RESUMO

In the search for new antiviral therapies against human immunodeficiency virus type 1 (HIV-1), several cellular targets are being investigated. Ataxia telangiectasia and Rad3-related protein (ATR) has been implicated in HIV-1 replication, namely during retroviral DNA integration. We studied the effect of the ATR inhibitor ETP-46464 on HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and in the persistently HIV-1-infected cell line H61-D. After treatment with ETP-46464, a significant decrease in virus production was observed in both cell systems. Quantification of viral DNA forms in the acutely infected PBMCs suggests that inhibition could take place in the early phase of the viral life cycle before viral DNA integration. Moreover, after treatment of H61-D cells with 3'-azido-3'-deoxythymidine (AZT), which blocks new reverse transcription events, ETP-46464 decreased viral production, suggesting that inhibition of viral replication occurred in the late phase of the life cycle after viral DNA integration. A decrease in virus production after transfection of 293T cells with an HIV-1 infectious molecular clone also suggested that the effect of ETP-46464 is exerted at a post-integration step. We propose that ETP-46464 produces its inhibitory effect on HIV-1 replication by acting in both the early and late phases of the retroviral replication cycle. Thus, ATR could represent a new target for inhibition of HIV-1 replication.


Assuntos
Antivirais/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Oxazinas/farmacologia , Quinolinas/farmacologia , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Humanos
2.
Nat Commun ; 11(1): 164, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919360

RESUMO

Host dependency factors that are required for influenza A virus infection may serve as therapeutic targets as the virus is less likely to bypass them under drug-mediated selection pressure. Previous attempts to identify host factors have produced largely divergent results, with few overlapping hits across different studies. Here, we perform a genome-wide CRISPR/Cas9 screen and devise a new approach, meta-analysis by information content (MAIC) to systematically combine our results with prior evidence for influenza host factors. MAIC out-performs other meta-analysis methods when using our CRISPR screen as validation data. We validate the host factors, WDR7, CCDC115 and TMEM199, demonstrating that these genes are essential for viral entry and regulation of V-type ATPase assembly. We also find that CMTR1, a human mRNA cap methyltransferase, is required for efficient viral cap snatching and regulation of a cell autonomous immune response, and provides synergistic protection with the influenza endonuclease inhibitor Xofluza.


Assuntos
Predisposição Genética para Doença/genética , Interações Hospedeiro-Patógeno/genética , Vírus da Influenza A/patogenicidade , Influenza Humana/genética , Influenza Humana/patologia , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Antivirais/farmacologia , Sistemas CRISPR-Cas , Linhagem Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/genética , Metiltransferases/metabolismo , Proteínas do Tecido Nervoso/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , ATPases Vacuolares Próton-Translocadoras/metabolismo , Internalização do Vírus
3.
Eur J Med Chem ; 187: 111960, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869654

RESUMO

A series of l-lysine-conjugated pyridophenoxazinones 2-5 and 2'-5' were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV-vis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5'-GC-3' base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo IIα over Topo IIß and stimulate the formation of covalent Topo II-DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone-l-lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/efeitos dos fármacos , Lisina/farmacologia , Oxazinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Modelos Lineares , Lisina/química , Modelos Moleculares , Estrutura Molecular , Oxazinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
4.
J Enzyme Inhib Med Chem ; 35(1): 50-58, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31656107

RESUMO

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).


Assuntos
Hipoglicemiantes/farmacologia , Oxazinas/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 185: 111771, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31671309

RESUMO

This work describes a straightforward diastereoselective synthetic access to azirino[2,1-b]benzo[e][1,3]oxazines containing phosphorus substituents such as phosphonate or phosphine oxide, by means of nucleophilic addition of functionalized phenols to the C-N double bond of 2H-azirine derivatives. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. Some azirino[2,1-b]benzo[e][1,3]oxazines 4 and 6 exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been detected.


Assuntos
Antineoplásicos/farmacologia , Oxazinas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Fosforilação , Relação Estrutura-Atividade
6.
Chem Commun (Camb) ; 55(80): 12036-12039, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31531454

RESUMO

While commercially available suncare products are effective at absorbing ultraviolet (UV)-light, recent studies indicate systemic toxicities associated with many traditional chemical and physical UV-filters. We demonstrate the application of xanthommatin, a biochrome present in arthropods and cephalopods, as an alternative chemical UV-filter that is cytocompatible while maintaining its photostability and photoprotective properties.


Assuntos
Antioxidantes/farmacologia , Oxazinas/farmacologia , Pele/efeitos da radiação , Protetores Solares/farmacologia , Xantenos/farmacologia , Animais , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Dimetilpolisiloxanos/química , Humanos , Camundongos , Células NIH 3T3 , Oxazinas/química , Estudo de Prova de Conceito , Pele/citologia , Protetores Solares/química , Raios Ultravioleta , Xantenos/química
7.
Malar J ; 18(1): 237, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307493

RESUMO

BACKGROUND: Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated. METHODS: Six acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model. RESULTS: All the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain. CONCLUSIONS: The six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound.


Assuntos
Antimaláricos/farmacologia , Oxazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/toxicidade , Células HEK293 , Células Hep G2 , Humanos , Oxazinas/toxicidade , Testes de Toxicidade
8.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146356

RESUMO

Experimental studies have shown that ligands of the 18 kDa translocator protein can reduce neuronal damage induced by traumatic brain injury by protecting mitochondria and preventing metabolic crisis. Etifoxine, an anxiolytic drug and 18 kDa translocator protein ligand, has shown beneficial effects in the models of peripheral nerve neuropathy. The present study investigates the potential effect of etifoxine as a neuroprotective agent in traumatic brain injury (TBI). For this purpose, the effect of etifoxine on lesion volume and modified neurological severity score at 4 weeks was tested in Sprague-Dawley adult male rats submitted to cortical impact contusion. Effects of etifoxine treatment on neuronal survival and apoptosis were also assessed by immune stains in the perilesional area. Etifoxine induced a significant reduction in the lesion volume compared to nontreated animals in a dose-dependent fashion with a similar effect on neurological outcome at four weeks that correlated with enhanced neuron survival and reduced apoptotic activity. These results are consistent with the neuroprotective effect of etifoxine in TBI that may justify further translational research.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Oxazinas/uso terapêutico , Animais , Proteínas de Transporte/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo
9.
Int J Mol Sci ; 20(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226783

RESUMO

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.


Assuntos
Cinamatos/uso terapêutico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Tiazóis/uso terapêutico , Tiofenos/uso terapêutico , Trombocitopenia/tratamento farmacológico , Animais , Cinamatos/química , Cinamatos/farmacologia , Desenvolvimento de Medicamentos , Humanos , Oxazinas/química , Oxazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Tiazóis/química , Tiazóis/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Trombocitopenia/metabolismo
10.
Pestic Biochem Physiol ; 157: 1-12, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153457

RESUMO

The use of neurotoxic chemical insecticides has led to consequences against the environment, insect resistances and side-effects on non-target organisms. In this context, we developed a novel strategy to optimize insecticide efficacy while reducing doses. It is based on nanoencapsulation of a pyrethroid insecticide, deltamethrin, used as synergistic agent, combined with a non-encapsulated oxadiazine (indoxacarb). In this case, the synergistic agent is used to increase insecticide efficacy by activation of calcium-dependant intracellular signaling pathways involved in the regulation of the membrane target of insecticides. In contrast to permethrin (pyrethroid type I), we report that deltamethrin (pyrethroid type II) produces an increase in intracellular calcium concentration in insect neurons through the reverse Na/Ca exchanger. The resulting intracellular calcium rise rendered voltage-gated sodium channels more sensitive to lower concentration of the indoxacarb metabolite DCJW. Based on these findings, in vivo studies were performed on the cockroach Periplaneta americana and mortality rates were measured at 24 h, 48 h and 72 h after treatments. Comparative studies of the toxicity between indoxacarb alone and indoxacarb combined with deltamethrin or nanoencapsulated deltamethrin (LNC-deltamethrin), indicated that LNC-deltamethrin potentiated the effect of indoxacarb. We also demonstrated that nanoencapsulation protected deltamethrin from esterase-induced enzymatic degradation and led to optimize indoxacarb efficacy while reducing doses. Moreover, our results clearly showed the benefit of using LNC-deltamethrin rather than piperonyl butoxide and deltamethrin in combination commonly used in formulation. This innovative strategy offers promise for increasing insecticide efficacy while reducing both doses and side effects on non-target organisms.


Assuntos
Cálcio/metabolismo , Inseticidas/química , Inseticidas/farmacologia , Nanocápsulas/química , Nitrilos/química , Nitrilos/farmacologia , Oxazinas/química , Oxazinas/farmacologia , Piretrinas/química , Piretrinas/farmacologia , Animais , Células Cultivadas , Baratas , Masculino , Estrutura Molecular , Periplaneta/efeitos dos fármacos , Trocador de Sódio e Cálcio/metabolismo
11.
PLoS One ; 14(5): e0217307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107922

RESUMO

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunocompetência , Hospedeiro Imunocomprometido , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Replicação Viral/efeitos dos fármacos
12.
Am J Health Syst Pharm ; 76(11): 789-794, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-30951590

RESUMO

PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety, dosing and administration, and place in therapy of fostamatinib, a novel spleen tyrosine kinase inhibitor for the treatment of adult immune thrombocytopenia that has had an insufficient response to a previous treatment are summarized. SUMMARY: Fostamatinib is an oral inhibitor of spleen tyrosine kinase that is expressed on hematopoietic cells and plays a key role in the accelerated destruction of platelets through Fc-receptor activation. Fostamatinib is indicated for the treatment of adults with immune thrombocytopenia that has had an insufficient response to a previous treatment. In 2 parallel, identically designed, placebo-controlled Phase III trials, patients with persistent and chronic immune thrombocytopenia treated with fostamatinib demonstrated clinically meaningful responses in platelet counts with lower rates of moderate and severe bleeding-related adverse events. Overall, fostamatinib therapy is generally well tolerated; the most common adverse events reported in clinical trials were diarrhea, nausea, hypertension, liver function test elevations, and infection. Being primarily metabolized through the CYP3A4 pathway, fostamatinib is subject to drug-drug interactions and concomitant administration with strong CYP3A4 inhibitors or inducers can affect fostamatinib exposure. CONCLUSION: Fostamatinib is a first-in-class spleen tyrosine kinase inhibitor approved for the treatment of adults with immune thrombocytopenia that has had an insufficient response to a previous treatment.


Assuntos
Plaquetas/efeitos dos fármacos , Oxazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Piridinas/farmacologia , Quinase Syk/antagonistas & inibidores , Administração Oral , Plaquetas/imunologia , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Oxazinas/uso terapêutico , Contagem de Plaquetas , Inibidores de Proteínas Quinases/uso terapêutico , Púrpura Trombocitopênica Idiopática/imunologia , Piridinas/uso terapêutico , Receptores Fc/imunologia , Receptores Fc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Quinase Syk/metabolismo , Resultado do Tratamento
14.
J Renin Angiotensin Aldosterone Syst ; 20(1): 1470320319827449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30813831

RESUMO

INTRODUCTION:: AZD9977 is a novel mineralocorticoid receptor (MR) modulator, which in preclinical studies demonstrated organ protection without affecting aldosterone-regulated urinary electrolyte excretion. However, when tested in humans, using fludrocortisone as an MR agonist, AZD9977 exhibited similar effects on urinary Na+/K+ ratio as eplerenone. The aim of this study is to understand whether the contradictory results seen in rats and humans are due to the mineralocorticoid used. MATERIALS AND METHODS:: Rats were treated with single doses of AZD9977 or eplerenone in combination with either aldosterone or fludrocortisone. Urine was collected for five to six hours and total amounts excreted Na+ and K+ were assessed. RESULTS:: AZD9977 dose-dependently increased urinary Na+/K+ ratio in rats when tested against fludrocortisone, but not when tested against aldosterone. Eplerenone dose-dependently increased urinary Na+/K+ ratio when tested against fludrocortisone as well as aldosterone. CONCLUSIONS:: The data suggest that the contrasting effects of AZD9977 on urinary electrolyte excretion observed in rats and humans are due to the use of the synthetic mineralocorticoid fludrocortisone. Future clinical studies are required to confirm the reduced electrolyte effects of AZD9977 and the subsequent lower predicted hyperkalemia risk.


Assuntos
Aldosterona/farmacologia , Benzoatos/farmacologia , Fludrocortisona/farmacologia , Mineralocorticoides/farmacologia , Oxazinas/farmacologia , Receptores de Mineralocorticoides/metabolismo , Aldosterona/administração & dosagem , Animais , Benzoatos/administração & dosagem , Eplerenona/farmacologia , Fludrocortisona/administração & dosagem , Humanos , Oxazinas/administração & dosagem , Potássio/urina , Ratos , Sódio/urina
15.
ChemMedChem ; 14(6): 645-662, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30702807

RESUMO

Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure-activity relationships.


Assuntos
Inibidores Enzimáticos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazinas , Timidilato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Oxazinas/síntese química , Oxazinas/química , Oxazinas/farmacologia , Relação Estrutura-Atividade
16.
PLoS One ; 14(2): e0207733, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794538

RESUMO

We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 µM against Mycobacterium tuberculosis, SI = 9.8). Here, we found that the compound is bactericidal towards Mycobacterium smegmatis, resulting in greater than 5 Log10 reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 µM (4X MIC) concentration. Growth inhibition (MIC = 50 µM) and reduction in cfu could also be observed against a clinical isolate of Mycobacterium abscessus. Stepwise isolation of resistant mutants of M. smegmatis was conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibits Mtb topoisomerase I and Mtb gyrase with IC50 of 0.24 and 27 µM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC50 for inhibition of Mtb topoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of Mtb topoisomerase I.


Assuntos
Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Mycobacterium/efeitos dos fármacos , Oxazinas/farmacologia , Antibacterianos/química , Antibacterianos/uso terapêutico , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Resistência Microbiana a Medicamentos/genética , Fluoroquinolonas/química , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium/classificação , Mycobacterium/genética , Mycobacterium/isolamento & purificação , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/genética , Mycobacterium abscessus/isolamento & purificação , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Oxazinas/química , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Sequenciamento Completo do Genoma
17.
Int Immunopharmacol ; 68: 39-47, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611000

RESUMO

Acute lung injury (ALI) is one of the most serious complications in critically ill patients which often leads to morbidity and mortality. ALI characterized by severe inflammation of lungs occurs due to uncontrolled inflammatory immune response. However, the immunological mechanism(s) are far from being understood. The spleen tyrosine kinase (SYK), a key component of immune receptor signaling, plays a critical role in the modulation of inflammatory signaling in different immune cells. However, its role in ALI remains to be explored. Therefore, in this study, we investigated the effect of R406, a SYK inhibitor in lipopolysaccharide (LPS)-induced ALI mouse model. LPS led to increased SYK expression in neutrophils and gamma delta (γδ) T cells. This was associated with increased neutrophilic airway inflammation, vascular permeability, myeloperoxidase activity in the lung with upregulated expression of NADPH oxidase (NOX2)/MCP-1/TNF-α in neutrophils and IL-17A in γδ T cells/lung. Pulmonary inflammation was associated with higher mortality in mice with ALI. Inhibition of SYK signaling using R406 in the lung led to blockade of neutrophilic airway inflammation, vascular permeability, pro-inflammatory cytokine release and oxidative stress in innate immune cells, i.e. γδ T cells and neutrophils and the lung. R406 administered LPS group had better survival rate than LPS group. This suggests that SYK upregulation in γδ T cells and neutrophils plays an important role in inflammatory process during ALI. In conclusion, R406 exhibited a great potential to block the LPS-induced airway inflammation and mortality which could be developed as a potential future therapy in ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Interleucina-17/antagonistas & inibidores , NADPH Oxidases/antagonistas & inibidores , Oxazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Quinase Syk/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/farmacologia , Linfócitos Intraepiteliais/efeitos dos fármacos , Linfócitos Intraepiteliais/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Oxazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia
18.
Rev Esp Quimioter ; 32(1): 1-5, 2019 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-30676002

RESUMO

Baloxavir marboxil (5-hydroxy-4-pyridone-3-carboxyl acid) is a new antiviral drug with special efficacy on influenza viruses that acts by inhibiting the cap-dependent endonuclease required for its replication. It is the first representative of the so-called inhibitors of influenza-like PB2. It has shown efficacy against influenza viruses A and B and most strains of animal origin (avian flu). Clinical trials conducted in healthy patients between 12 and 64 years without pathologies and not hospitalized (mild flu) have shown a reduction in the duration of symptoms similar to that obtained by oseltamivir. However, baloxavir is a much more potent inhibitor of viral replication than this drug. It has been shown as a safe and well tolerated drug. A single dose of 40-80 mg is administered the first 48 hours after onset of symptoms. In these trials, strains with moderate sensitivity (PA / I38T mutants) were detected in 2.2% of influenza A (H1N1) pdm09 and in 9.7% of influenza A (H3N2). Although these data could be a good drug to treat mild or moderate influenza, requiring trials in severe influenza and patients with chronic diseases to establish their true clinical utility.


Assuntos
Antivirais/uso terapêutico , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/enzimologia , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Adulto , Antivirais/farmacologia , Criança , Feminino , Humanos , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Adulto Jovem
19.
Colloids Surf B Biointerfaces ; 176: 371-378, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30658285

RESUMO

Nile Red-loaded nanostructured lipid carriers (NR-NLCs), prepared by high-pressure homogenization technique, have been investigated for their transcorneal penetration using a confocal scanning microfluorometer (CSMF). Topical exposure of NR-NLCs led to their penetration into the epithelium and anterior stroma. The NR-NLC-40 (NR-NLCs of 40 nm) showed faster penetration compared to NR-NLC-150 (NR-NLCs of 150 nm). The surface modification of NR-NLC-40 with polyethylene glycol 400 (NR-NLC-PEG) and stearylamine (NR-NLC-SA), although did not cause any significant effect on size, resulted in an increased penetration into the epithelium concomitant with a reduced penetration into the stroma compared to the NR-NLC-40. Ex vivo mucoadhesion assay revealed that NR-NLC-PEG and NR-NLC-SA adhered more strongly to the porcine corneal surface compared to NR-NLC-40. Flow cytometry experiments with porcine corneal epithelial cells showed that NR-NLC-40 was internalized better than NR-NLC-PEG and NR-NLC-SA. These results, taken together, suggest that NLCs are potentially useful for lipophilic drug delivery to the corneal epithelium and anterior stroma without any surface modifications. However, surface modifications with polyethylene glycol 400 or stearylamine could be useful to treat ocular surface disorders.


Assuntos
Córnea/efeitos dos fármacos , Lipídeos/química , Nanoestruturas/química , Oxazinas/farmacologia , Animais , Endocitose/efeitos dos fármacos , Fluorescência , Tamanho da Partícula , Eletricidade Estática , Propriedades de Superfície , Suínos , Fatores de Tempo
20.
PLoS One ; 14(1): e0210879, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30668583

RESUMO

In a previously published study, higher levels of spleen tyrosine kinase (Syk) were observed in recurrent post-chemotherapy ovarian cancers compared to primary tumors. Syk inhibition was found to stabilize microtubules and potentiate paclitaxel activity in cellular models of taxane-resistant ovarian cancers. We further studied the effects of Syk inhibition on paclitaxel activity in Syk(+) ovarian cancer cell models and in variants selected for taxane resistance. Syk inhibition was accomplished using RNAi and by exposure to the small molecule competitive inhibitor R406, the active metabolite of fostamatinib. Exposure to R406 or to a SYK-specific pool of siRNAs did not alter taxane activity in the OVCAR-3 cell line, which has the most Syk content in our panel of nine human ovarian cancer cell lines. However, treatment with R406 sensitised the multidrug resistant (MDR) variants MES-SA/Dx5 and SK-OV-3/TR to paclitaxel in a dose-dependent manner resulting from the inhibition of the ABCB1/P-glycoprotein (P-gp) drug transporter. These observations are Syk-independent since both MDR cell models are Syk negative. R406 modulated resistance to other known P-gp substrates, and we observed orthovanadate-sensitive ATPase stimulation resulting from treatment with R406. These data indicate that the chemo-sensitizing effect of R406 in taxane-resistant cells previously reported was not associated with Syk but resulted from the modulation of P-gp-mediated MDR.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Quinase Syk/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , RNA Interferente Pequeno/genética , Quinase Syk/genética , Taxoides/farmacologia
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