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1.
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
2.
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
3.
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
4.
Eur J Med Chem ; 168: 263-282, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822714

RESUMO

The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 µg/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Fenotiazinas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Triazóis/farmacologia , Adsorção , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Cercopithecus aethiops , Relação Dose-Resposta a Droga , Desenho de Drogas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenotiazinas/química , Fenotiazinas/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismo , Células Vero
5.
Artigo em Inglês | MEDLINE | ID: mdl-30857466

RESUMO

The current research article involves one pot synthesis of novel substituted 1-nitro-10H-phenothiazines via Smiles rearrangement. These substituted phenothiazines undergo oxidation to yield 10H-phenothiazine-5,5-dioxides (sulfones) while on treatment with ß-D-ribofuranose-1-acetate-2,3,5-tribenzoate yield ribofuranosides. These compounds were screened for their antimicrobial vitalities (in vitro) against selected strains of bacteria and fungi. The characterization of synthesized compounds was done by elemental and spectral studies.


Assuntos
Anti-Infecciosos/síntese química , Nitrocompostos/síntese química , Nucleosídeos/química , Fenotiazinas/síntese química , Sulfonas/química , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/química , Benzoatos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrocompostos/farmacologia , Oxirredução , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia
6.
Int J Mol Sci ; 20(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813251

RESUMO

Since none of the multidrug resistance (MDR) modulators tested so far found their way into clinic, a novel approach to overcome the MDR of cancer cells has been proposed. The combined use of two MDR modulators of dissimilar mechanisms of action was suggested to benefit from the synergy between them. The effect of three phenothiazine derivatives that were used as single agents and in combination with simvastatin on cell growth, apoptosis induction, activity, and expression of cyclooxygenase-2 (COX-2) in doxorubicin-resistant colon cancer cells (LoVo/Dx) was investigated. Treatment of LoVo/Dx cells by phenothiazine derivatives combined with simvastatin resulted in an increase of doxorubicin cytotoxicity and its intracellular accumulation as compared to the treatment with phenothiazine derivatives that were used as single agents. Similarly, LoVo/Dx cells treated with two-component mixture of modulators showed the reduced expression of ABCB1 (P-glycoprotein) transporter and COX-2 enzyme, both on mRNA and protein level. Reduced expression of anti-apoptotic Bcl-2 protein and increased expression of pro-apoptotic Bax were also detected. Additionally, COX-2 activity was diminished, and caspase-3 activity was increased to a higher extent by phenothiazine derivative:simvastatin mixtures than by phenothiazine derivatives themselves. Therefore, the introduction of simvastatin strengthened the anti-MDR, anti-inflammatory, and pro-apoptotic properties of phenothiazines in LoVo/Dx cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/química , Sinergismo Farmacológico , Humanos , Fenotiazinas/química , Sinvastatina/química , Sinvastatina/farmacologia , Proteína X Associada a bcl-2/metabolismo
7.
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
8.
Eur J Pharmacol ; 849: 124-134, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30721703

RESUMO

The idea of the use of anticancer drugs together with a chemosensitizer emerged as the strategy of reversal of multidrug resistance (MDR) of cancer cells expressing ABC proteins many years ago. The approaches relying on the use of a single chemosensitizer have never resulted in a clinical success. Therefore, the application of drug combinations of two or more compounds with different mechanisms of action might be an alternative approach to increase the success rate. In the present study the cytotoxic and NF-κB inhibition potential of the phenothiazine derivative, MAE-TPR, was evaluated. MAE-TPR was demonstrated to be an effective doxorubicin-resistance modulator in human adenocarcinoma cell line LoVo/Dx. In the presence of MAE-TPR cytotoxicity of doxorubicin was elevated, and its intracellular accumulation increased. Strong synergism occurred between MAE-TPR and Dox. MAE-TPR diminished also the expression of ABCB1 transporter (P-glycoprotein) by affecting NF-κB pathway. Theobromine, a phytochemical from cocoa, which was barely active itself, strongly augmented MDR reversal potency of MAE-TPR. The effect of the combination of phenothiazine derivative with theobromine on cancer cells was studied for the first time in the present work. It was concluded that the use of the proposed combination of two modulators might be a promising strategy for MDR reversal since modulators could be used in concentrations much lower than in case of their single application and in that way the risk of intolerable side-effects could be reduced.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cacau/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Fenotiazinas/química , Fenotiazinas/farmacologia , Teobromina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , NF-kappa B/metabolismo , Teobromina/química
9.
Molecules ; 24(2)2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30642021

RESUMO

New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell lines, depending on the nature of the substituents. The most active 3,6-diazaphenothiazine, 4, was the derivative with the N,N-diethylamino-2-butynyl substituent against glioblastoma SNB-19, and was ten times more potent than cisplatin. For this compound, the expression of H3, TP53, CDKN1A, BCL-2, and BAX genes was detected by the RT-qPCR method. The gene expression ratio BAX/BCL-2 indicated the induction of mitochondrial apoptosis in cancer cell lines. The transformation of the propynyl substituent into amino-2-butynyl can be a method applicable to the search for more anticancer-active azaphenothiazines.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fenotiazinas/síntese química , Fenotiazinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fenotiazinas/química
10.
Life Sci ; 219: 190-198, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30658098

RESUMO

AIMS: To initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor. MATERIALS AND METHODS: We have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle. KEY FINDINGS: After a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C-23 °C. The hypothermic state may continue on average for 16-17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4-8 days later they were restored. SIGNIFICANCE: Suspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.


Assuntos
Hipotermia/induzido quimicamente , Torpor/efeitos dos fármacos , Animais , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Difenidramina/administração & dosagem , Difenidramina/farmacologia , Combinação de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas , Ivabradina/administração & dosagem , Ivabradina/farmacologia , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/farmacologia , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Fenotiazinas/administração & dosagem , Fenotiazinas/farmacologia , Fosfolipídeos/administração & dosagem , Fosfolipídeos/farmacologia , Propranolol/administração & dosagem , Propranolol/farmacologia , Propiltiouracila/administração & dosagem , Propiltiouracila/farmacologia , Ratos , Ratos Wistar , Reserpina/administração & dosagem , Reserpina/farmacologia , Taxa Respiratória/efeitos dos fármacos , Serotonina/administração & dosagem , Serotonina/farmacologia , Sorbitol/administração & dosagem , Sorbitol/farmacologia , Xenônio/administração & dosagem , Xenônio/farmacologia
11.
Photodiagnosis Photodyn Ther ; 25: 197-203, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30586617

RESUMO

Fusarium keratoplasticum and Fusarium moniliforme are filamentous fungi common in the environment and cause mycosis in both animals and plants. Human infections include mycetoma, keratitis and onychomycosis, while deeper mycosis occurs in immunocompromised patients. Most of the Fusarium spp. are frequently resistant to treatment with currently used antifungals. The frequent occurrence of antifungal resistance has motivated the study of antimicrobial photodynamic therapy as an alternative treatment for fungal infections. Many studies have investigated the in vitro use of antimicrobial photodynamic therapy to kill fungi, but rarely in animal models of infection. Thus, here we employed the invertebrate wax moth Galleria mellonella to study the in vivo effects of antimicrobial photodynamic therapy with three different phenothiazinium photosensitizers, methylene blue, new methylene blue N and the pentacyclic S137 against infection with microconidia of Fusarium keratoplasticum and Fusarium moniliforme. The effect of antimicrobial photodynamic therapy using these photosensitizers and light-emitting diodes with an emission peak at 635 nm and an integrated irradiance from 570 to 670 nm of 9.8 mW cm-2 was investigated regarding the toxicity, fungal burden, larval survival and cellular immune response. The results from this model indicate that antimicrobial photodynamic therapy with methylene blue, new methylene blue N and S137 is efficient for the treatment of infection with F. keratoplasticum and F. moniliforme. The efficiency can be attributed to the fungal cell damage caused by antimicrobial photodynamic therapy which facilitates the action of the host immune response.


Assuntos
Fusarium/efeitos dos fármacos , Fenotiazinas/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Animais , Antifúngicos/farmacologia , Dipeptídeos/farmacologia , Farmacorresistência Fúngica , Larva/efeitos dos fármacos , Lasers Semicondutores/uso terapêutico , Azul de Metileno/análogos & derivados , Azul de Metileno/farmacologia , Mariposas , Pirimidinas/farmacologia
12.
Chem Asian J ; 13(18): 2611-2618, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-29963750

RESUMO

The development of effective bioanalytical methods for rapid, sensitive and specific detection of HOCl in vitro and in vivo plays a key role for better understanding the roles of this molecule in normal and diseased conditions, but remains challenging due to the highly reactive nature of HOCl and the complicated biological conditions. In this work, a new fluorescence probe, PQI, was developed for monitoring of the HOCl level in biological samples. PQI was easily synthesized by a one-step condensation reaction. Upon addition of HOCl, significant changes in the absorption spectra and the color of the solution were noticed, facilitating the "naked eye" detection of HOCl in PBS buffer. The fluorescence of PQI was found to be significantly increased within a few seconds, leading to "OFF-ON" fluorescence response towards HOCl. The sensing mechanism, oxidation of thioether by HOCl, was confirmed by HRMS titration analysis. PQI features a large Stokes shift, high sensitivity and selectivity, and rapid fluorescence response towards HOCl. Quantitative detection of HOCl in single live cells was demonstrated through fluorescence imaging and flow cytometry analysis. PQI was then successfully used in visualisation of HOCl in live zebrafish and nude mice.


Assuntos
Corantes Fluorescentes/farmacologia , Ácido Hipocloroso/análise , Fenotiazinas/farmacologia , Compostos de Quinolínio/farmacologia , Animais , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Humanos , Concentração de Íons de Hidrogênio , Ácido Hipocloroso/química , Luz , Limite de Detecção , Células MCF-7 , Camundongos Nus , Imagem Óptica/métodos , Oxirredução , Fenotiazinas/síntese química , Fenotiazinas/química , Fenotiazinas/efeitos da radiação , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Compostos de Quinolínio/efeitos da radiação , Peixe-Zebra
13.
Molecules ; 23(6)2018 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-29843370

RESUMO

We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound 9f showed the most potent inhibitory effect against MCF-7 cells, with an IC50 value of 0.8 µM. Importantly, compound 9f could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.


Assuntos
Antineoplásicos/síntese química , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/genética , Fenotiazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , Fenotiazinas/química , Fenotiazinas/farmacologia , Relação Estrutura-Atividade
14.
Int Immunopharmacol ; 59: 276-286, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29674255

RESUMO

The therapeutic efficacy of topically applied azaphenothiazine derivatives: 9-chloro-6-acetylaminobutylquinobenzo[3,2-b][1,4]thiazine (compound 4) and 6-chloroethylureidoethyldiquino[3,2-b;2';3'-e][1,4]thiazine (compound 5) in the amelioration of inflammatory symptoms of imiquimod-induced psoriasis in mice was investigated. Clobederm®, containing clobetasol propioniate, served as a reference drug. The application of the compounds led to thinning of the epidermis and reduction of the cell layers. The suppressive actions of the compounds were even stronger with regard to pathological changes of the dermis. The compounds also exerted generalized, anti-inflammatory effects by decreasing the number of circulating leukocytes, lowering subiliac lymph node weight and partially normalizing an altered blood cell composition. The changes in the composition of main cell types in the epidermis and dermis were less affected by the compounds. In addition, both compounds inhibited to a similar degree production of tumor necrosis factor α (TNF α) in human whole blood cell culture. Whereas compound 5 strongly inhibited IL-8 and CXCL10 chemokines in human keratinocytes - KERTr cell line, transfected with poly(I:C), the suppressive action of compound 4 in this model was weak. In addition, compound 5, but not compound 4, exhibited at low doses proapoptotic properties with regard to colonic cell lines. In summary, we demonstrated the therapeutic potential of two selected azaphenotiazines in the amelioration of the skin pathology elicited in a mouse experimental model of psoriasis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fenotiazinas/uso terapêutico , Psoríase/tratamento farmacológico , Administração Tópica , Aminoquinolinas , Animais , Anti-Inflamatórios/farmacologia , Caspases/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HCT116 , Humanos , Imiquimode , Células Jurkat , Contagem de Leucócitos , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fenotiazinas/farmacologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Receptor fas/metabolismo
15.
Photodiagnosis Photodyn Ther ; 22: 96-100, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29499391

RESUMO

The aim of this study was to evaluate the lethal potential of macrophages infected with Staphylococcus aureus after PACT (Photochemical Antimicrobial Chemotherapy) using phenothiazine derivatives (a solution containing 1:1 methylene blue and O toluidine blue) and laser (660 nm, 40 mW, 60 s, 12 J/cm2) or LED (632 ±â€¯2 nm, 145 mW, 40 s, 12 J/cm2). Six experimental groups were evaluated: Control Group (untreated); Photosensitizer group (phenothiazines - 12.5 µg/mL); Laser Group; LED Group; Laser PACT Group; and LED PACT Group. The pre-irradiation time used in this study was 5 min. Macrophages and bacteria were cultured in specific culture media and/or allowed interaction between the cell types. Subsequently, tests were carried out to evaluate microbial proliferation, ROS production by macrophages and survival capacity of S. aureus after phagocytosis. Fluorescence microscopy assays were performed with the H2DCFDA probe, after PACT, at the initial time (0 h), 4-h and 12-h. The tests were performed in triplicate and the statistical test used was ANOVA with Tukey post-test. After PACT, a statistically significant difference (p > 0.0001) was observed between the microbial growth of the control group and the PACTs groups. Laser PACT and LED PACT groups presented, respectively, reductions of 84.2% and 81.5% when compared to control and 53.3% and 46% when compared to the photosensitizer group. It is concluded that the therapeutic protocols presented in this study increased the phagocytic capacity, the response rate of the phagocytes and the consequent reduction of the numbers of S. aureus for both PACT protocols, however the increase in ROS production was only observed in the group irradiated with Laser light.


Assuntos
Macrófagos/efeitos dos fármacos , Fenotiazinas/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Luz , Macrófagos/microbiologia , Azul de Metileno/farmacologia , Microscopia de Fluorescência , Cloreto de Tolônio/farmacologia
16.
Sci Rep ; 8(1): 1650, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374224

RESUMO

Developing peripherally active cannabinoid 1 (CB1) receptor antagonists is a novel therapeutic approach for the management of obesity. An unusual phenothiazine scaffold containing CB1R antagonizing hit was identified by adopting virtual screening work flow. The hit so identified was further modified by introducing polar functional groups into it to enhance the polar surface area and decrease the hydrophobicity of the resulting molecules. CB1 receptor antagonistic activity for the designed compounds was computed by the previously established pharmacophore and three dimensional quantitative structure-activity relationship models. Docking studies of these designed compounds confirmed the existence of favourable interactions within the active site of the CB1 receptor. The designed compounds were synthesized and evaluated for their CB1 receptor antagonistic activity. Parallel artificial membrane permeability assay was performed to evaluate their potential to permeate into the central nervous system wherein it was observed that the compounds did not possess the propensity to cross the blood brain barrier and would be devoid of central nervous system side effects. In pharmacological evaluation, the synthesized compounds (23, 25, 27 and 34) showed significant decrease in food intake suggesting their potential application in the management of obesity through CB1 receptor antagonist activity.


Assuntos
Fármacos Antiobesidade/farmacologia , Fenotiazinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/síntese química , Comportamento Alimentar/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Fenotiazinas/administração & dosagem , Fenotiazinas/síntese química , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Ratos Wistar
17.
Mini Rev Med Chem ; 18(17): 1442-1451, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28486909

RESUMO

The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs acting through different mechanisms are in dire need to counter the resistant strains. Various chemical scaffolds are being investigated against tuberculosis, among them the molecules containing phenothiazine nucleus are found to be more effective against both susceptible and resistant strains of M. tuberculosis. In addition, the efficacy of first-line drugs has been found to be enhanced on supplementary treatment with phenothiazines. The present review provides an overview of the phenothiazine based molecules which were investigated during the last ten years for their anti-tubercular activity.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fenotiazinas/farmacologia , Tuberculose/tratamento farmacológico , Antituberculosos/química , Humanos , Testes de Sensibilidade Microbiana , Fenotiazinas/química
18.
Histol Histopathol ; 33(2): 223-236, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28748525

RESUMO

In this work we investigated the efficacy of two topically applied azaphenothiazine derivatives, 9-chloro-6-acetylaminobutylquinobenzo[3,2-b][1,4]thiazine (compound 4) and 6-chloroethylureidoethyldiquino[3,2-b;2';3'-e][1,4]thiazine (compound 5), in the amelioration of inflammatory symptoms of contact sensitivity (CS) to oxazolone in mice, in relation to the commercial ointment Protopic® (tacrolimus), the reference drug. The compounds were administered 24 h following elicitation of CS and, 24 h later, the parameters of inflammation, such as ear edema, blood composition, leukocyte level, numbers of cells in the draining lymph nodes, histological picture of the inflamed tissue, and the morphometric analysis, were analyzed. The study showed that the effectiveness of the studied azaphenothiazines applied as a 0.1% ointment was comparable to the reference drug regarding suppression of the inflammatory process, when all the investigated histological parameters are taken into account.


Assuntos
Adjuvantes Imunológicos/toxicidade , Dermatite de Contato/prevenção & controle , Pomadas/farmacologia , Oxazolona/toxicidade , Fenotiazinas/farmacologia , Administração Tópica , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C
19.
Drug Des Devel Ther ; 11: 3045-3063, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29123378

RESUMO

The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H-3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 µM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (ΔΨm) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-κB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the Matrigel™ Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Fenotiazinas/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HEK293 , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Concentração Inibidora 50 , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Invasividade Neoplásica , Fenotiazinas/administração & dosagem , Fenotiazinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
20.
Anticancer Res ; 37(11): 5983-5993, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29061777

RESUMO

Phenothiazines have been used in many areas of medicine, mainly in psychopharmacology. These compounds are able to effectively inhibit dopamine, histamine, serotonin, acetylcholine, and α-adrenergic receptors; thus, their effect and side-effect profiles are extremely diverse. Besides their antipsychotic activity, phenothiazines have a significant antimicrobial effect as well, since they can enhance the bactericidal function of macrophages and inhibit efflux pumps. They are also able to eliminate bacterial resistance plasmids and destroy bacteria by their membrane-destabilizing effect. Their antiviral, antiprotozoal, antifungal, and antiprion activities have also been described. Phenothiazines have also been proven to destroy cancer cells and sensitize them to chemotherapy. Anti-angiogenesis and anticancer stem cell activities have also been reported, and they might be applied as adjuvants in the treatment of infections and tumors in the future. Finally, phenothiazines can also be effective in the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antipsicóticos/farmacologia , Fenotiazinas/farmacologia , Animais , Humanos , Infecção/tratamento farmacológico , Transtornos Mentais/tratamento farmacológico , Neoplasias/tratamento farmacológico
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