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1.
Eur J Pharmacol ; 887: 173553, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949606

RESUMO

In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.


Assuntos
Antipsicóticos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fenotiazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Animais , Antipsicóticos/uso terapêutico , Antivirais/uso terapêutico , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Flufenazina/farmacologia , Flufenazina/uso terapêutico , Humanos , Pandemias , Perfenazina/farmacologia , Perfenazina/uso terapêutico , Fenotiazinas/uso terapêutico , Proclorperazina/farmacologia , Proclorperazina/uso terapêutico , Tioridazina/farmacologia , Tioridazina/uso terapêutico
2.
PLoS One ; 15(9): e0222548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32870913

RESUMO

The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or T-cell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-É£) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells. Here we demonstrate that allosteric inhibition of MALT1 suppressed Th1, Th17 and Th1/Th17 effector responses, and inhibited T-cell dependent B-cell proliferation and antibody production. Allosteric MALT1 inhibition did not interfere with the suppressive function of human T-regulatory cells, although it impaired de novo differentiation of regulatory T-cells from naïve T-cells. Treatment with an allosteric MALT1 inhibitor alleviated the cytokine storm, including IFN-É£, in a mouse model of acute T-cell activation, and long-term treatment did not lead to an increase in IFN-É£ producing CD4 cells or tissue inflammation. Together, our data demonstrate that the effects of allosteric inhibition of MALT1 differ from those seen in mice with proteolytically inactive MALT1, and thus we believe that MALT1 is a viable target for B and T-cell driven autoimmune diseases.


Assuntos
Linfócitos B/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Transferência Ressonante de Energia de Fluorescência , Voluntários Saudáveis , Humanos , Injeções Intraperitoneais , Interferon gama/imunologia , Interferon gama/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Fenotiazinas/farmacologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo
3.
Anticancer Res ; 40(9): 4921-4928, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878780

RESUMO

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/patologia , Camundongos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Fenotiazinas/síntese química , Fenotiazinas/química
4.
J Photochem Photobiol B ; 211: 111997, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32829256

RESUMO

The worldwide infection with the new Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) demands urgently new potent treatment(s). In this study we predict, using molecular docking, the binding affinity of 15 phenothiazines (antihistaminic and antipsychotic drugs) when interacting with the main protease (Mpro) of SARS-CoV-2. Additionally, we tested the binding affinity of photoproducts identified after irradiation of phenothiazines with Nd:YAG laser beam at 266 nm respectively 355 nm. Our results reveal that thioridazine and its identified photoproducts (mesoridazine and sulforidazine) have high biological activity on the virus Mpro. This shows that thioridazine and its two photoproducts might represent new potent medicines to be used for treatment in this outbreak. Such results recommend these medicines for further tests on cell cultures infected with SARS-CoV-2 or animal model. The transition to human subjects of the suggested treatment will be smooth due to the fact that the drugs are already available on the market.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fenotiazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/efeitos da radiação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Humanos , Lasers de Estado Sólido , Simulação de Acoplamento Molecular , Pandemias , Fenotiazinas/química , Fenotiazinas/efeitos da radiação , Processos Fotoquímicos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
5.
Chem Biol Interact ; 324: 109092, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278739

RESUMO

Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger that protects from the toxicity of nerve agents. Non-human primates are suitable models for toxicity studies that cannot be performed in humans. We evaluated the biochemical properties of native macaque (MaBChE) tetramers, compared to recombinant MaBChE monomers, PEGylated recombinant MaBChE tetramers and monomers, and native HuBChE tetramers. Km and kcat values for butyrylthiocholine were independent of subunit assembly status. The Km for all forms of MaBChE was about 70 µM, compared to 13 µM for HuBChE. The kcat was about 100,000 min-1 for MaBChE and 30,000 min-1 for HuBChE. The reversible inhibitor ethopropazine had similar Ki values of 0.05 µM for all MaBChE forms and HuBChE. The bimolecular rate constant, ki, for inhibition by diisopropylfluorophosphate (DFP), an analog of sarin, was 2.2 to 2.5 × 107 M-1 min-1 for all MaBChE forms and for HuBChE. A major difference between MaBChE and HuBChE was the rate of reactivation by 2-PAM. The second order rate constant for reactivation of DFP-inhibited MaBChE by 2-PAM was 1.4 M-1 min-1, but was 380 fold faster for DFP-inhibited HuBChE (kr 531 M-1 min-1). The acyl pocket of MaBChE has Leu285 in place of Pro285 in HuBChE. The reactivation rate of DFP-inhibited HuBChE mutant P285L by 2-PAM was reduced 5.8-fold (kr 92 M-1 min-1) indicating that P285 determines whether 2-PAM binds in an orientation that favors release of diisopropylphosphate. DFP-inhibited MaBChE treated with 0.2 M 2-PAM recovered 10% of its original activity, whereas DFP-inhibited HuBChE recovered 80% activity. It was concluded that the biochemical properties of MaBChE are similar to those of HuBChE except for the reactivation of DFP-inhibited BChE.


Assuntos
Butirilcolinesterase/química , Reativadores da Colinesterase/química , Compostos de Pralidoxima/química , Prolina/química , Sequência de Aminoácidos , Animais , Inibidores da Colinesterase/farmacologia , Humanos , Cinética , Macaca , Macaca mulatta , Fenotiazinas/farmacologia , Alinhamento de Sequência
6.
PLoS Negl Trop Dis ; 14(3): e0007790, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32168320

RESUMO

Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction or stabilization of the procyclin transcript. Using these bloodstream reporter strains in combination with automated flow cytometry, we identified eflornithine, spironolactone, and phenothiazine as small molecules that increase abundance of procyclin transcript. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. While we failed to identify compounds that increase levels of procyclin protein on the cell surface, this study is proof of principle that these fluorescent reporter parasites represent a useful tool for future small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/crescimento & desenvolvimento , Avaliação Pré-Clínica de Medicamentos/métodos , Eflornitina/farmacologia , Fenotiazinas/farmacologia , Espironolactona/farmacologia
7.
Int J Cancer ; 146(6): 1618-1630, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31291468

RESUMO

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.


Assuntos
Biperideno/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Fenotiazinas/farmacologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/biossíntese , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/química , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-rel/metabolismo , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Lasers Med Sci ; 35(1): 79-85, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31081523

RESUMO

Chagas disease is endemic in Latin America and increasingly found in non-endemic countries. Its treatment is limited due to the variable efficacy and several side effects of benznidazole. Photodynamic antimicrobial chemotherapy (PACT) may be an attractive approach for treating Chagas disease. Here, the trypanocidal activity of PACT was investigated in vitro using phenothiazine derivatives. The cytotoxicity of both, methylene blue (MB) and toluidine blue (TBO), was determined on macrophages cultures using AlamarBlue method. The trypanocidal activity of the two photosensitizers was initially evaluated by determining their IC50 values against trypomastigote forms. After this, the trypanocidal effect was evaluated in cultures of infected macrophages using an automatized image analysis protocol. All experiments were performed in the dark and in the clear phase (after a photodynamic exposure). The compounds showed no cytotoxicity in both phases at the tested concentrations. The IC50 values for the sole use of MB and TBO were 2.6 and 1.2 µM, respectively. The photoactivation of the compounds using a fixed energy density (J/cm2) caused a reduction of the IC50 values to 1.0 and 0.9 µM, respectively. It was found that, on infected macrophage, the use of TBO significantly reduced the number of infected cells and parasitic load, and this effect was increased in the presence of light. The results of the present study are indicative that PACT may be considered as both selective and effective therapeutic intervention for treating Chagas disease.


Assuntos
Antiparasitários/farmacologia , Fenotiazinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Anti-Infecciosos/farmacologia , Antiparasitários/uso terapêutico , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Doença de Chagas/tratamento farmacológico , Humanos , Luz , Azul de Metileno/química , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Camundongos Endogâmicos BALB C , Carga Parasitária , Fenotiazinas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Cloreto de Tolônio/química , Cloreto de Tolônio/farmacologia , Cloreto de Tolônio/uso terapêutico , Trypanosoma cruzi/efeitos da radiação
9.
Molecules ; 24(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801304

RESUMO

A series of novel 1,2,3-triazole-diazphenothiazine hybrids was designed, synthesized, and evaluated for anticancer activity against four selected human tumor cell lines (SNB-19, Caco-2, A549, and MDA-MB231). The majority of the synthesized compounds exhibited significant potent activity against the investigated cell lines. Among them, compounds 1d and 4c showed excellent broad spectrum anticancer activity, with IC50 values ranging from 0.25 to 4.66 µM and 0.25 to 6.25 µM, respectively. The most promising compound 1d, possessing low cytotoxicity against normal human fibroblasts NHFF, was used for gene expression analysis using reverse transcription-quantitative real-time PCR (RT-qPCR). The expression of H3, TP53, CDKN1A, BCL-2, and BAX genes revealed that these compounds inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Fenotiazinas/química , Fenotiazinas/farmacologia , Triazóis/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fenotiazinas/síntese química , Relação Estrutura-Atividade
10.
Sci Rep ; 9(1): 19311, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848419

RESUMO

In this study, we develop a real-time PCR strategy to directly detect and quantify DNA aptamers on functionalized graphene surfaces using a Staphylococcus aureus aptamer (SA20) as demonstration case. We show that real-time PCR allowed aptamer quantification in the range of 0.05 fg to 2.5 ng. Using this quantitative technique, it was possible to determine that graphene functionalization with amino modified SA20 (preceded by a graphene surface modification with thionine) was much more efficient than the process using SA20 with a pyrene modification. We also demonstrated that the functionalization methods investigated were selective to graphene as compared to bare silicon dioxide surfaces. The precise quantification of aptamers immobilized on graphene surface was performed for the first time by molecular biology techniques, introducing a novel methodology of wide application.


Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais , Grafite/química , Reação em Cadeia da Polimerase em Tempo Real , Ouro/química , Fenotiazinas/farmacologia , Staphylococcus aureus/química , Propriedades de Superfície
11.
Eur J Med Chem ; 183: 111692, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541872

RESUMO

A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the treatment of breast cancer. Phenothiazine derivatives (l) did not noticeably inhibit the growth of SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, whereas phenothiazine derivatives (ll) containing the NO donor were more potent or had comparable inhibitory activity to trifluoperazine (TFP) and thioridazine against SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells. Compounds 20a-c and 21a-c showed the strongest activity in SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, and more potent inhibitory activity than TFP against KG1a cells (IC50 = 1.63, 2.93, 1.14, 1.78, 2.20, and 1.20 vs. 4.58 µM). Compounds 20a and 21a had lower toxicity than compounds 20b-c and 21b-c, and inhibited colony formation in MCF-7 cells, decreased the formation of mammospheres in SUM159 cells, and inhibited the migration of MDA-MB-231 cells. Compounds 20a and 21a could inhibited pNF-κB-p65 as shown by dual-luciferase reporter assays and western blotting in MDA-MB-231 cells.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Fenotiazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade
12.
Photodiagnosis Photodyn Ther ; 28: 75-79, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31470119

RESUMO

AIM: Diode lasers are commonly used for antimicrobial photodynamic therapy (aPDT). This study aimed to assess the feasibility of transgingival laser irradiation during aPDT and evaluate whether the photosensitizer can be activated. MATERIALS AND METHODS: Four diode laser settings were assessed for transgingival irradiation: 120 mW, 80 mW, 60 mW, and 40 mW. Fifteen soft-tissue pieces from a pig's lower jaw were prepared. The specimens' thickness was measured and transgingival laser irradiation was performed. A digital power meter measured laser power on the other side of the tissue. The power outcome after staining of the nonbuccal aspect of the tissue with photosensitizer dye was assessed similarly. RESULTS: Transgingival laser irradiation (average soft-tissue thickness: 0.84 ±â€¯0.06 mm) resulted in different power transmission depending on the power settings and photosensitizer. The lowest values were observed with the 40 mW setting and photosensitizer (median 3.3 mW, max. 5.0 mW, min. 2.3 mW, interquartile range 1.2), and the highest at 120 mW without photosensitizer (median 41.3 mW, max. 42.7 mW, min. 38.0 mW; interquartile range 1.5). CONCLUSIONS: This study indicates that transgingival irradiation may be suitable for aPDT, since power transmission through the gingival tissue was observed in all specimens. However, the decrease in laser power caused by both the soft tissue and the photosensitizer has to be taken into account.


Assuntos
Gengiva/efeitos dos fármacos , Lasers Semicondutores , Fenotiazinas/farmacologia , Fotoquimioterapia/instrumentação , Fármacos Fotossensibilizantes/farmacologia , Animais , Gengiva/efeitos da radiação , Técnicas In Vitro , Suínos
13.
Biomed Res Int ; 2019: 8301569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355283

RESUMO

Chagas disease is a tropical illness caused by the protozoan Trypanosoma cruzi. The disease affects populations of the Americas and has been spread to other continents due to the migration process. The disease is partially controlled by two drugs, Benznidazole and Nifurtimox. These molecules are active in the acute phase of the infection but are usually ineffective during the symptomatic chronic phase. Several research groups have developed novel candidates to control Chagas disease; however, no novel commercial formulation is available. In this article, we described the anti-T. cruzi effects of phenothiazinium dyes in amastigote and trypomastigote forms of the parasite. Methylene Blue, New Methylene Blue, Toluidine Blue O, and 1,9-Dimethyl Methylene Blue inhibited the parasite proliferation at nanomolar concentrations and also demonstrated low toxicity in host cells. Moreover, combinations of phenothiazinium dyes indicated a synergic pattern against amastigotes compared to the Benznidazole counterparts. Phenothiazinium dyes levels of reactive oxygen species (ROS) and decreased the mitochondrial potential in trypomastigotes, indicating the mechanism of action of the dyes in T. cruzi. Our article offers a basis for future strategies for the control of Chagas disease using low-cost formulations, an important point for endemic underdeveloped regions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Fenotiazinas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Doença de Chagas/parasitologia , Corantes/farmacologia , Humanos , Azul de Metileno/análogos & derivados , Azul de Metileno/farmacologia , Nifurtimox/farmacologia , Nitroimidazóis/farmacologia , Cloreto de Tolônio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/patogenicidade
14.
Int J Oncol ; 55(2): 536-546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268158

RESUMO

Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet­derived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern­matching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine­class drugs). Western blot analysis demonstrated that all four drugs had ETV1­downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellular­signal­regulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.


Assuntos
Biomarcadores Tumorais/genética , Conectoma , Proteínas de Ligação a DNA/antagonistas & inibidores , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fenotiazinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Apoptose , Proteínas de Ligação a DNA/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Perfilação da Expressão Gênica , Humanos , Prognóstico , Transdução de Sinais , Fatores de Transcrição/genética
15.
J Enzyme Inhib Med Chem ; 34(1): 1298-1306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307242

RESUMO

10H-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced 1H and 13C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and N, N-diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of H3, TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).


Assuntos
Antineoplásicos/farmacologia , Fenotiazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
Chem Asian J ; 14(22): 4035-4041, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31251464

RESUMO

Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure-activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.


Assuntos
Mitocôndrias/metabolismo , Oligopeptídeos/metabolismo , Fenotiazinas/química , Survivina/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Citocromos c/metabolismo , Humanos , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Fenotiazinas/metabolismo , Fenotiazinas/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade , Survivina/química
17.
J Microbiol Immunol Infect ; 52(4): 638-647, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31239204

RESUMO

BACKGROUND: The emergence of multiple-antibiotic-resistant (MAR) Salmonella has been a serious threat worldwide. Salmonella can invade into host cells and evade the attacks of host humoral defenses and antibiotics. Thus, a new antibacterial agent capable of inhibiting intracellular Salmonella is highly needed. METHODS: The anti-intracellular activity and cytotoxicity of drugs on intracellular bacteria and macrophages were assayed using intracellular CFU assay and MTT cell viability assay, respectively. The uptake of gentamicin into macrophage and the effect of autophagy inhibitor on loxapine's anti-intracellular Salmonella activity were assessed by using image-based high-content system. The expression of bacterial genes was measured by real-time PCR. The efflux pump activity of bacteria was measured by Hoechst accumulation assays. RESULTS: With our efforts, an antipsychotic drug, loxapine, was identified to exhibit high potency in suppressing intracellular MAR S. Typhimurium, Staphylococcus aureus, Shigella flexneri or Yersinia enterocolitica. Subsequent investigations indicated that loxapine's anti-intracellular bacteria activity was not associated with increased penetration of gentamicin into bacteria and macrophages. Loxapine didn't inhibit bacterial growth in broth at concentration up to 500 µM and has no effect on Salmonella's type III secretion system genes' expression. Blockage of autophagy also didn't reverse loxapine's anti-intracellular activity. Lastly, loxapine suppressed bacterial efflux pump activity in all bacteria tested. CONCLUSION: Altogether, our data suggested that loxapine might suppress intracellular bacteria through inhibiting of bacterial efflux pumps. In light of its unique activity, loxapine represents a promising lead compound with translational potential for the development of a new antibacterial agent against intracellular bacteria.


Assuntos
Antibacterianos/farmacologia , Antipsicóticos/farmacologia , Loxapina/farmacologia , Macrófagos/microbiologia , Salmonella typhimurium/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Proteínas de Bactérias/genética , Sobrevivência Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Gentamicinas/farmacologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Camundongos , Testes de Sensibilidade Microbiana , Fenotiazinas/farmacologia , Células RAW 264.7 , Salmonella typhimurium/genética , Salmonella typhimurium/crescimento & desenvolvimento , Sorogrupo , Shigella flexneri/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Sistemas de Secreção Tipo III/efeitos dos fármacos , Sistemas de Secreção Tipo III/genética , Yersinia enterocolitica/efeitos dos fármacos
18.
Photochem Photobiol Sci ; 18(6): 1576-1586, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31066390

RESUMO

We report herein the physicochemical properties and antimicrobial activity of a new monobrominated derivative of Azure B and its parent compound. These dyes are used as photosensitizers for photodynamic therapy and photodynamic antimicrobial chemotherapy. Relevant pharmaceutical properties (pKa, chemical and photochemical stability, and in vitro antimicrobial activity) were determined. A UV-visible spectrophotometry method was developed and validated according to the International Conference on Harmonization (ICH) guidelines for use in stability indicating studies and determination of the acid dissociation constant of Azure B and its monobrominated derivative. The results showed that both dyes were chemically stable. In addition, bromination of the phenothiazine dye decreased its photochemical stability and pKa value without affecting the ionization rate at physiological pH. The analytical parameters for validation of the method were linearity (r2 > 0.9981), limit of detection (LOD) (0.2-0.9 µM), limit of quantification (LOQ) (0.6-2.7 µM), and intra-day precision (0.76-1.40%) expressed as relative standard deviation (RSD). Recoveries ranging from 99.5 to 100.9% were obtained for the two dyes. Thus, this method provides a simple, sensitive, accurate, and precise assay for the determination of all compounds. The effect of photosensitizer concentration and visible irradiation time on lethal photosensitization against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was investigated. Both photosensitizers were active against the evaluated bacteria. However, the new monobrominated derivative was more effective than its predecessor and managed to eradicate these microorganisms by using different doses of the dye and light. In other words, a lower concentration of AzBBr and irradiation time were required to cause bacterial death equal to or greater than its precursor. The photodynamic efficacy of the two photosensitizers presented the following order: S. aureus > E. coli > P. aeruginosa. These studies indicated that the tested dyes satisfy the conditions of potential photosensitizers in terms of physicochemical and antimicrobial properties.


Assuntos
Antibacterianos/farmacologia , Fenotiazinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antibacterianos/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenotiazinas/química , Fármacos Fotossensibilizantes/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Nat Microbiol ; 4(6): 972-984, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30911127

RESUMO

Bacterial virulence factors are attractive targets for the development of therapeutics. Type IV pili, which are associated with a remarkable array of properties including motility, the interaction between bacteria and attachment to biotic and abiotic surfaces, represent particularly appealing virulence factor targets. Type IV pili are present in numerous bacterial species and are critical for their pathogenesis. In this study, we report that trifluoperazine and related phenothiazines block functions associated with Type IV pili in different bacterial pathogens, by affecting piliation within minutes. Using Neisseria meningitidis as a paradigm of Gram-negative bacterial pathogens that require Type IV pili for pathogenesis, we show that piliation is sensitive to altered activity of the Na+ pumping NADH-ubiquinone oxidoreductase (Na+-NQR) complex and that these compounds probably altered the establishment of the sodium gradient. In vivo, these compounds exert a strong protective effect. They reduce meningococcal colonization of the human vessels and prevent subsequent vascular dysfunctions, intravascular coagulation and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, they reduce lethality. This work provides a proof of concept that compounds with activity against bacterial Type IV pili could beneficially participate in the treatment of infections caused by Type IV pilus-expressing bacteria.


Assuntos
Fímbrias Bacterianas/efeitos dos fármacos , Fímbrias Bacterianas/fisiologia , Infecções Meningocócicas/prevenção & controle , Neisseria meningitidis/efeitos dos fármacos , Fatores de Virulência , Animais , Antibacterianos/farmacologia , Vasos Sanguíneos/lesões , Vasos Sanguíneos/microbiologia , Vasos Sanguíneos/patologia , Combinação de Medicamentos , Complexo I de Transporte de Elétrons , Feminino , Fímbrias Bacterianas/genética , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Bactérias Gram-Negativas , Humanos , Camundongos , Neisseria meningitidis/genética , Neisseria meningitidis/crescimento & desenvolvimento , Fenotiazinas/farmacologia , Pele/patologia , Transplante de Pele , ATPase Trocadora de Sódio-Potássio , Trifluoperazina/farmacologia
20.
Redox Biol ; 24: 101164, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30925294

RESUMO

Impaired mitochondrial function has been associated with the etiopathogenesis of Parkinson's disease (PD). Sustained inhibition of complex I produces mitochondrial dysfunction, which is related to oxidative injury and nigrostriatal dopamine (DA) neurodegeneration. This study aimed to identify disease-modifying treatments for PD. Unsubstituted phenothiazine (PTZ) is a small and uncharged aromatic imine that readily crosses the blood-brain barrier. PTZ lacks significant DA receptor-binding activity and, in the nanomolar range, exhibits protective effects via its potent free radical scavenging and anti-inflammatory activities. Given that DAergic neurons are highly vulnerable to oxidative damage and inflammation, we hypothesized that administration of PTZ might confer neuroprotection in different experimental models of PD. Our findings showed that PTZ rescues rotenone (ROT) toxicity in primary ventral midbrain neuronal cultures by preserving neuronal integrity and reducing protein thiol oxidation. Long-term treatment with PTZ improved animal weight, survival rate, and behavioral deficits in ROT-lesioned rats. PTZ protected DA content and fiber density in the striatum and DA neurons in the SN against the deleterious effects of ROT. Mitochondrial dysfunction, axonal impairment, oxidative insult, and inflammatory response were attenuated with PTZ therapy. Furthermore, we have provided a new insight into the molecular mechanism underlying the neuroprotective effects of PTZ.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NAD/metabolismo , Fenotiazinas/farmacologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Animais , Biomarcadores , Técnicas de Cultura de Células , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Masculino , Modelos Biológicos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Ratos , Rotenona/efeitos adversos
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